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This executive summary reviews the topics covered in this PDQ summary on cancer genetics risk assessment and genetic counseling, with hyperlinks to detailed sections below that describe the evidence on each topic.
Individuals are considered to be candidates for cancer risk assessment if they have a personal and/or family history (on the maternal or paternal side) or clinical characteristics with features suggestive of hereditary cancer. These features vary by type of cancer and specific hereditary syndrome. Criteria have been published to help identify individuals who may benefit from genetic counseling. It is important that individuals who are candidates for genetic testing undergo genetic education and counseling before testing to facilitate informed decision-making and adaptation to the risk or condition. Genetic education and counseling allows individuals to consider the various medical uncertainties, diagnosis, or medical management options based on varied test results, and the risks, benefits, and limitations of genetic testing.
Comprehensive cancer risk assessment and counseling is a consultative service that includes clinical assessment, genetic testing when appropriate, and risk management recommendations delivered in the context of one or more genetic counseling sessions. Pretest genetic counseling is an important part of the risk assessment process and helps patients understand their genetic testing options and potential outcomes. Posttest genetic counseling helps patients understand their test results, including the medical implications for themselves and their relatives.
The recommended provision of cancer risk assessment services optimally involves care providers from multiple disciplines, including a genetic counselor; a genetics advanced practice nurse; a medical geneticist or a physician, such as an oncologist, surgeon, or internist; and potential referrals to other specialists, such as mental health professionals, endocrinologists, and reproductive specialists.
Traditionally, genetic counseling services have been delivered using individualized, in-person appointments. However, other methodologies are being increasingly utilized, including group sessions, telephone counseling, and telemedicine by videoconferencing.
There are many factors that can influence an individual’s decision to undergo genetic testing and which type of test to use, including the presence of a known pathogenic variant in the family, patterns of cancer in the family, insurance coverage, family planning considerations, and the psychological impact of a test result. Previously, most germline genetic testing was offered for a single gene at a time; however, recent technological advances have resulted in the widespread availability of multigene (panel) testing, which can simultaneously test for pathogenic variants in many genes at once, often at costs comparable to single-gene testing. Research has examined the use and outcomes of multigene testing.
Some health-related cancer genetic tests are also offered as direct-to-consumer (DTC) tests. While these tests may promote access and patient autonomy, the process may not include genetic counseling or interpretation of the results by a genetics professional. In addition, these tests may be incomplete or require confirmation with a second DNA sample sent to another clinical laboratory.
Cascade genetic testing can be effective in identifying carriers of a pathogenic variant prior to cancer presentation which provides opportunities for cancer prevention, early detection, risk reduction, and ultimately improved health outcomes.
Various cancer genetic service delivery approaches are being used to facilitate greater access to genetic counseling and testing. These approaches have been utilized to streamline the process by which high-risk or affected individuals are identified and referred to specialty genetic services for additional evaluation. These service delivery models vary in the processes by which patients receive genetic education, counseling, and testing.
Having an understanding of the ethical, legal, and social implications regarding cancer genetic testing may influence the clinician’s response to the complex questions and issues that may arise during the process of risk assessment and counseling. There are several ethical and legal considerations that factor into decisions about what responsibility, if any, providers have to directly inform at-risk relatives about hereditary cancer risks. This section addresses duty to warn, including legal frameworks and available guidance from professional societies. Consultation with an ethicist, ethics committee, legal counsel, privacy officer, and when applicable, an institutional review board, may be warranted in certain disclosure situations.
Employment and insurance discrimination are common concerns for individuals considering genetic testing. The Genetic Information Nondiscrimination Act of 2008 (GINA), a Federal law passed in 2008, protects against health insurance and employment discrimination on the basis of genetics information for most people; however, it does not apply to members of the military or to long-term care, disability, and life insurance provisions.
[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]
[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term “variant” rather than the term “mutation” to describe a difference that exists between the person or group being studied and the reference sequence, particularly for differences that exist in the germline. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]
This summary describes current approaches to assessing and counseling people about their chance of having an inherited susceptibility to cancer. Genetic counseling is defined by the National Society of Genetic CounselorsExit Disclaimer as the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. Several reviews present overviews of the cancer risk assessment, counseling, and genetic testing process.[1,2]
Individuals are considered to be candidates for cancer risk assessment if they have a personal and/or family history (maternal or paternal lineage) with features suggestive of hereditary cancer.[1] These features vary by type of cancer and specific hereditary syndrome. Criteria have been published to help identify individuals who may benefit from genetic counseling.[1,3] The PDQ cancer genetics information summaries on breast, ovarian, endometrial, colorectal, prostate, kidney, and skin cancers and endocrine and neuroendocrine neoplasias describe the clinical features of hereditary syndromes associated with these conditions.
The following are features that suggest hereditary cancer:[4–8]
As part of the process of genetic education and counseling, genetic testing may be considered when the following factors are present:[9–11]
It is important that individuals who are candidates for genetic testing undergo genetic education and counseling before testing to facilitate informed decision making and adaptation to the risk or condition.[1,7–13] Genetic education and counseling allows individuals to consider the various medical uncertainties, diagnosis, or medical management based on varied test results, and the risks, benefits, and limitations of genetic testing.
After an individual’s personal and family cancer histories have been collected, several factors could warrant referral to a genetics professional for evaluation of hereditary cancer susceptibility syndromes. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors have published a comprehensive set of personal and family history criteriaExit Disclaimer to guide the identification of at-risk individuals and appropriate referral for cancer genetic risk consultation.[1] These practice guidelines take into account tumor types or other features and related criteria that would indicate a need for a genetics referral. The authors state that the guidelines are intended to maximize appropriate referral of at-risk individuals for cancer genetic consultation but are not meant to provide genetic testing or treatment recommendations.
Identification of patients at moderate to high risk of hereditary cancer for genetic services is recommended by all major societies. Primary care physicians have a number of tools available to triage patients. In addition to the published categorical guidelines available through professional organizations,[1–4] there are also red flag cards, paper-based checklists, and patient-directed online referral tools. Table 1 provides a list of several publicly available resources that can be used to identify patients for referral to genetic services. Although most tools are brief and simple enough for patients to complete on their own, either previsit, online, or in the waiting room, clinical review is warranted. Many include the commonly known features suggestive of hereditary cancers, but exclusions are noted in the table below.
| Name | Mode and Length (Referral Threshold) | Sensitivity/Specificity and Validation | Tool Completed By (Tested Setting) | Featuresa |
|---|---|---|---|---|
| aAll tools are available in English. Tools were tested in U.S. populations unless otherwise stated. | ||||
| bReferral yield in test population. | ||||
| Breast/Ovarian Cancer Tools for Health Professionals | ||||
| Breast cancer referral screening tool (B-RST) [5] | • Paper or OnlineExit Disclaimer | Sensitivity 81%/Specificity 92% | Health professional (mammography clinic) | Does not include bilateral breast cancer or breast and ovarian cancer in the same person. 6% high riskb. |
| • 2-column table (2 positive answers) | Validated in other populations [6-8] | |||
| Family health screening questionnaire [9] | • Paper | Sensitivity 95%/Specificity 54% | Health professional (primary care) | Tested in Australia. Does not include bilateral breast cancer or breast and ovarian cancer in the same person. |
| • 9 questions (1 positive answer) | ||||
| Family history assessment tool (FHAT) [10] | • Paper | Not provided | Health professional (primary care) | Tested in Canada. Includes colon and prostate cancers. Includes third-degree relatives. |
| • 12 questions (>10 points for family score) | ||||
| FHS-7 [11] | • Paper | Sensitivity 87%/Specificity 54% | Health professional (primary care) | Tested in community-based population in Brazil. 6% high riskb. |
| • 7 questions (1 positive answer) | ||||
| Pedigree assessment tool (PAT) [12] | • Paper | Sensitivity 100%/Specificity 93% | Health professional (primary care) | Tested in community hospital. |
| • 5 items (≥8 points) | Validated in other populations [13] | |||
| Breast/Ovarian Cancer Tools for Patients | ||||
| “Are you at risk for hereditary breast cancer?” educational brochure [14] | • Paper | Not provided | Patient (breast and cervical cancer screening clinic) | Tested in underinsured or uninsured low-income women. |
| • 11 questions (1 positive answer) | ||||
| Family history questionnaire [15] | • Paper | Not provided | Patient (mammography clinic) | Tested in Australia. Does not include ovarian cancer, male breast cancer, or bilateral breast cancer. 13% high riskb. |
| • 6 questions (about 3 positive answers) | ||||
| 6-point scale [16] | • Paper | Sensitivity 27%/Specificity 97% | Patient (mammography clinic) | Tested in low-income women in a safety net setting. |
| • 10 questions (≥6 points) | ||||
| Colon Cancer Tools | ||||
| FHS-7 [11] | • Paper | Sensitivity 87%/Specificity 54% | Health professional (primary care) | Tested in community-based population in Brazil. 6% high riskb. |
| • 7 questions (1 positive answer) | ||||
| Lynch syndrome risk assessment tool [17] | • Paper | Not provided | Patient (colonoscopy clinic) | 3% high riskb. |
| • 7 questions (1 positive answer) | ||||
There are also more extensive statistical risk assessment models designed for both highly motivated patients [18,19] and genetic specialists (e.g., CancerGeneExit Disclaimer, IBISExit Disclaimer).
References
Comprehensive cancer risk assessment is a consultative service that includes clinical assessment, genetic testing when appropriate, and risk management recommendations delivered in the context of one or more genetic counseling sessions. Pretest genetic counseling is an important part of the risk assessment process and helps patients understand their genetic testing options and potential outcomes. Posttest genetic counseling helps patients understand their test results, including the medical implications for themselves and their relatives.
The following professional organizations emphasize the importance of genetic counseling in the cancer risk assessment and genetic testing process:
A list of organizations that have published clinical practices guidelines related to genetic counseling, risk assessment, genetic testing, and/or management for hereditary breast and ovarian cancers is available in the PDQ summary on Genetics of Breast and Gynecologic Cancers.
Genetic counseling informs the consultand about potential cancer risks and the benefits and limitations of genetic testing and offers an opportunity to consider the potential medical, psychological, familial, and social implications of genetic information.[9,18] Descriptions of genetic counseling and the specialized practice of cancer risk assessment counseling are detailed below.
Genetic counseling has been defined by the National Society of Genetic Counselors as the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease, including the following:[9]
Traditionally, genetic counseling services have been delivered using individualized in-person appointments. However, other methodologies have been implemented, including group sessions, telephone counseling, and online genetic counseling using remote videoconferencing, which is often referred to as telegenetics. (Refer to the Modalities of genetic counseling section of this summary for more information.)
Central to the philosophy and practice of genetic counseling are the principles of voluntary utilization of services, informed decision making, attention to psychosocial and affective dimensions of coping with genetic risk, and protection of patient confidentiality and privacy. This is facilitated through a combination of rapport building and information gathering; establishing or verifying diagnoses; risk assessment and calculation of quantitative occurrence/recurrence risks; education and informed consent processes; psychosocial assessment, support, and counseling appropriate to a family’s culture and ethnicity; and other relevant background characteristics.[19,20] The psychosocial assessment is especially important in the genetic counseling process because individuals most vulnerable to adverse effects of genetic information may include those who have had difficulty dealing with stressful life events in the past.[21] Variables that may influence psychosocial adjustment to genetic information include individual and familial factors; cultural factors; and health system factors such as the type of test, disease status, and risk information.[21] Findings from a psychosocial assessment can be used to help guide the direction of the counseling session.[10] An important objective of genetic counseling is to provide an opportunity for shared decision making when the medical benefits of one course of action are not demonstrated to be superior to another. The relationship between the availability of effective medical treatment for carriers of pathogenic variants and the clinical validity of a given test affects the degree to which personal choice or physician recommendation is supported in counseling at-risk individuals.[22] Uptake of genetic counseling services among those referred varies based on the cancer syndrome and the clinical setting. Efforts to decrease barriers to service utilization are ongoing (e.g., the use of a patient navigator or an oncology clinic–based genetic counselor may increase utilization of these services).[23–25] Readers interested in the nature and history of genetic counseling are referred to a number of comprehensive reviews.[26–31]
Cancer risk assessment counseling has emerged as a specialized practice that requires knowledge of genetics, oncology, and individual and family counseling skills that may be provided by health care providers with this interdisciplinary training.[32] Some centers providing cancer risk assessment services involve a multidisciplinary team, which may include a genetic counselor; a genetics advanced practice nurse; a medical geneticist or a physician, such as an oncologist, surgeon, or internist; and a mental health professional.
References
This section provides an overview of critical elements in the cancer risk assessment process.
A number of professional guidelines on the elements of cancer genetics risk assessment and counseling are available.[1–5] Except where noted, the discussion below is based on these guidelines.
The cancer risk assessment and genetic counseling process consists of one or more consultative sessions and generally includes the following:
At the outset of the initial counseling session, eliciting and addressing the consultand’s perceptions and concerns about cancer and his or her expectations of the risk assessment process helps to engage the consultand in the session. This also helps inform the provider about practical or psychosocial issues and guides the focus of counseling and strategies for risk assessment.
The counseling process that takes place as part of a cancer risk assessment can identify factors that contribute to the consultand’s perception of cancer risk and motivations to seek cancer risk assessment and genetic testing. It can also identify potential psychological issues that may need to be addressed during or after the session, particularly after genetic testing. Information collected before and/or during the session may include the following:
Either alone or in consultation with a mental health provider, health care providers offering cancer risk counseling attempt to assess whether there are factors suggesting risk of adverse psychological outcomes after disclosure of risk and/or genetic status.
Perceived risk can play an important role in an individual’s decision to participate in counseling,[6] despite the fact that perceived risk often varies substantially from statistical risk estimates.[7–9]
Consideration of the consultand’s personal health history is essential in cancer risk assessment, regardless of whether the individual has a personal history of cancer. Important information to obtain about the consultand’s health history includes the following:[1,3]
For consultands with a history of cancer, additional information collected includes the following:
In some cases, a physical exam is conducted by a qualified medical professional to determine whether the individual has physical findings suggestive of a hereditary cancer predisposition syndrome or to rule out evidence of an existing malignancy. For example, a medical professional may look for the sebaceous adenomas seen in Muir-Torre syndrome, measure the head circumference or perform a skin exam to rule out benign cutaneous features associated with Cowden syndrome, or perform a clinical breast and axillary lymph node exam on a woman undergoing a breast cancer risk assessment.
The family history is an essential tool for cancer risk assessment. The family history can be obtained via interview or written self-report; both were found to result in equivalent information.[10] Studies suggest that paper-based family history questionnaires completed before the appointment provide accurate family history information [11] and that the use of these questionnaires is an acceptable and understandable family history collection method.[12] Both multimedia-based (e.g., Internet) and print-based (e.g., family history questionnaires) tools are currently available to gather information about family history. However, on average, print-based tools have been found to be written at lower reading grade levels than multimedia-based tools.[13] It has been reported that questionnaire-based assessments may lead to some underreporting of family history; therefore, a follow-up interview to confirm the reported information and to capture all relevant family history information may be required.[14] Collecting family history from multiple relatives in a single family has been shown to increase the number of family members reported to have cancer, compared with family history information provided by a single family member.[15]
Details of the family health history are best summarized in the form of a family tree, or pedigree. The pedigree, a standardized graphic representation of family relationships, facilitates identification of patterns of disease transmission, recognition of the clinical characteristics associated with specific hereditary cancer syndromes, and determination of the best strategies and tools for risk assessment.[16,17]
Standards of pedigree nomenclature have been established.[16,17] Refer to Figure 1 for common pedigree symbols.
Figure 1. Standard pedigree nomenclature. Common symbols are used to draw a pedigree (family tree). A pedigree shows relationships between family members and patterns of inheritance for certain traits and diseases.
Refer to the paragraph below for descriptions of factors suggesting inherited cancer risk.
Documentation of a comprehensive family cancer history typically includes the following:
A three-generation family history includes the following:
For any relative with cancer, collect the following information:[19]
For relatives not affected with cancer, collect the following information:
The accuracy of the family history has a direct bearing on determining the differential diagnoses, selecting appropriate testing, interpreting results of the genetic tests, refining individual cancer risk estimates, and outlining screening and risk reduction recommendations. In a telephone survey of 1,019 individuals, only 6% did not know whether a first-degree relative had cancer; this increased to 8.5% for second-degree relatives.[20] However, people often have incomplete or inaccurate information about the cancer history in their family.[17,19,21–27] Patient education has been shown to improve the completeness of family history collection and may lead to more-accurate risk stratification, referrals for genetic counseling, and changes to management recommendations.[28] Confirming the primary site of cancers in the family that will affect the calculation of hereditary predisposition probabilities and/or estimation of empiric cancer risks may be important, especially if decisions about treatments such as risk-reducing surgery will be based on this family history.[23,29]
Accuracy varies by cancer site and degree of relatedness.[25,30,31] Reporting of cancer family histories may be most accurate for breast cancer [25,31] and less accurate for gynecologic malignancies [25,31] and colon cancer.[25] Self-reported family histories may contain errors and, in rare instances, could be fictitious.[23,29,31] The most reliable documentation of cancer histology is the pathology report. Verification of cancers can also be made through other medical records, tumor registries, or death certificates.
Because a family history of cancer is one of the important predictors of cancer risk, analysis of the pedigree constitutes an important aspect of risk assessment. This analysis might be thought of as a series of the following questions:
The clues to a hereditary syndrome are based on pedigree analysis and physical findings. The index of suspicion is raised by the following:[18]
Clinical characteristics associated with different cancer genetic syndromes are summarized in the following comprehensive set of personal and family history criteriaExit Disclaimer published by the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors.[32] These practice guidelines take into account tumor types or other features and related criteria that would indicate a need for a genetics referral. The authors state that the guidelines are intended to maximize appropriate referral of at-risk individuals for cancer genetic consultation but are not meant to provide genetic testing or treatment recommendations.
The most commonly encountered indications for genetic counseling/testing are for suspected hereditary breast cancer or hereditary colon cancer syndromes.
For hereditary breast cancer, genetic counseling and testing criteria are broad.[32,33] Multigene panel testing has revealed that pathogenic variants in several other high- and moderate-penetrance genes other than BRCA1 and BRCA2 contribute to this phenotype, such as PALB2, CHEK2, and ATM.
For hereditary colon cancer syndromes, differential diagnoses are based on several factors, including the number and type of colorectal polyps and histopathology of gastrointestinal and other malignancies.[34,35] However, in the absence of polyposis and rare pathologies, Lynch syndrome is frequently in the differential. Furthermore, Lynch syndrome may be in the differential diagnoses list even when there are cases of breast and/or ovarian cancer in the family that are not consistent with hereditary breast and ovarian cancer.[36,37] (Refer to the Lynch syndrome section in the PDQ summary on Genetics of Colorectal Cancer for more information.)
Diagnostic and testing criteria exist for several rare syndromes such as Li-Fraumeni,[38] Cowden,[39,40] multiple endocrine neoplasias,[41] and familial adenomatous polyposis.[34] In some cases, pathognomonic features are also an indicator for a likely diagnosis.[39,40]
Based on these considerations, genetic testing options may consist of limited targeted testing for pathogenic variants in one or a small number of genes, or may consist of larger gene panels.
Other factors may complicate recognition of basic inheritance patterns or represent different types of disease etiology.[42–44]
Common examples of complicating factors related to family history structure include the following:
Genetic factors that may affect family history interpretation include:
The mode of inheritance refers to the way that genetic traits are transmitted in the family.
Most commonly, inheritance patterns are established by a combination of clinical diagnosis with a compatible, but not necessarily in itself conclusive, pedigree pattern.[45] Most recognized hereditary cancer syndromes are autosomal dominant or autosomal recessive. Clues to recognizing these patterns within a pedigree are described below. (Refer to question 3, What could make the family history difficult to interpret?, for a list of situations that may complicate pedigree interpretation.)
Autosomal dominant
Autosomal recessive
Complex
Clustering of cancer among relatives is common, but teasing out the underlying causes when there is no clear pattern is more difficult. With many common malignancies, such as lung cancer, an excess of cancers in relatives can be seen. These familial aggregations are seen as being due to combinations of exposures to known carcinogens, such as tobacco smoke, and to pathogenic variants in high penetrance genes or alterations in genes with low penetrance that affect the metabolism of the carcinogens in question.[47]
The general practitioner is likely to encounter some families with a strong genetic predisposition to cancer and the recognition of cancer susceptibility may have dramatic consequences for a given individual’s health and management. Although some high-risk pathogenic variants in major cancer susceptibility genes are consistent with recognizable mendelian inheritance patterns, these syndromes are rare.
These probabilities vary by syndrome, family, gene, and pathogenic variant, with different variants in the same gene sometimes conferring different cancer risks, or the same variant being associated with different clinical manifestations in different families. These phenomena relate to issues such as penetrance and expressivity that are discussed elsewhere.
A positive family history may sometimes provide risk information in the absence of a specific genetically determined cancer syndrome. For example, the risk associated with having a single affected relative with breast or colorectal cancer can be estimated from data derived from epidemiologic and family studies. Examples of empiric risk estimates of this kind are provided in the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer.
The overarching goal of cancer risk assessment is to individualize cancer risk management recommendations based on personalized risk. Methods to calculate risk utilize health history information and risk factor and family history data often in combination with emerging biologic and genetic/genomic evidence to establish predictions.[48] Multiple methodologies are used to calculate risk, including statistical models, prevalence data from specific populations, penetrance data when a documented pathogenic variant has been identified in a family, mendelian inheritance, and Bayesian analysis. All models have distinct capabilities, weaknesses, and limitations based on the methodology, sample size, and/or population used to create the model. Methods to individually quantify risk encompass two primary areas: the probability of harboring a pathogenic variant in a cancer susceptibility gene and the risk of developing a specific form of cancer.[48]
The decision to offer genetic testing for cancer susceptibility is complex and can be aided in part by objectively assessing an individual’s and/or family’s probability of harboring a pathogenic variant.[49] Predicting the probability of harboring a pathogenic variant in a cancer susceptibility gene can be done using several strategies, including empiric data, statistical models, population prevalence data, Mendel’s laws, Bayesian analysis, and specific health information, such as tumor-specific features.[49,50] All of these methods are gene specific or cancer-syndrome specific and are employed only after a thorough assessment has been completed and genetic differential diagnoses have been established.
If a gene or hereditary cancer syndrome is suspected, models specific to that disorder can be used to determine whether genetic testing may be informative. (Refer to the PDQ summaries on the Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; or the Genetics of Skin Cancer for more information about cancer syndrome-specific probability models.) The key to using specific models or prevalence data is to apply the model or statistics only in the population best suited for its use. For instance, a model or prevalence data derived from a population study of individuals older than 35 years may not accurately be applied in a population aged 35 years and younger. Care must be taken when interpreting the data obtained from various risk models because they differ with regard to what is actually being estimated. Some models estimate the risk of a pathogenic variant being present in the family; others estimate the risk of a pathogenic variant being present in the individual being counseled. Some models estimate the risk of specific cancers developing in an individual, while others estimate more than one of the data above. Other important considerations include critical family constructs, which can significantly impact model reliability, such as small family size or male-dominated families when the cancer risks are predominantly female in origin, adoption, and early deaths from other causes.[42,50] In addition, most models provide gene and/or syndrome-specific probabilities but do not account for the possibility that the personal and/or family history of cancer may be conferred by an as-yet-unidentified cancer susceptibility gene.[43] In the absence of a documented pathogenic variant in the family, critical assessment of the personal and family history is essential in determining the usefulness and limitations of probability estimates used to aid in the decisions regarding indications for genetic testing.[43,49,50]
When a pathogenic variant has been identified in a family and a test report documents that finding, prior probabilities can be ascertained with a greater degree of reliability. In this setting, probabilities can be calculated based on the pattern of inheritance associated with the gene in which the pathogenic variant has been identified. In addition, critical to the application of mendelian inheritance is the consideration of integrating Bayes Theorem, which incorporates other variables, such as current age, into the calculation for a more accurate posterior probability.[1,51] This is especially useful in individuals who have lived to be older than the age at which cancer is likely to develop based on the pathogenic variant identified in their family and therefore have a lower likelihood of harboring the family pathogenic variant when compared with the probability based on their relationship to the carrier in the family.
Even in the case of a documented pathogenic variant on one side of the family, careful assessment and evaluation of the individual’s personal and family history of cancer is essential to rule out cancer risk or suspicion of a cancer susceptibility gene pathogenic variant on the other side of the family (maternal or paternal, as applicable).[52] Segregation of more than one pathogenic variant in a family is possible (e.g., in circumstances in which a cancer syndrome has founder pathogenic variants associated with families of particular ancestral origin).
Unlike pathogenic variant probability models that predict the likelihood that a given personal and/or family history of cancer could be associated with a pathogenic variant in a specific gene(s), other methods and models can be used to estimate the risk of developing cancer over time. Similar to pathogenic variant probability assessments, cancer risk calculations are also complex and necessitate a detailed health history and family history. In the presence of a documented pathogenic variant, cancer risk estimates can be derived from peer-reviewed penetrance data.[1] Penetrance data are constantly being refined and many genetic variants have variable penetrance because other variables may impact the absolute risk of cancer in any given patient. Modifiers of cancer risk in carriers of pathogenic variants include the variant’s effect on the function of the gene/protein (e.g., variant type and position), the contributions of modifier genes, and personal and environmental factors (e.g., the impact of bilateral salpingo-oophorectomy performed for other indications in a woman who harbors a BRCA pathogenic variant).[53] When there is evidence of an inherited susceptibility to cancer but genetic testing has not been performed, analysis of the pedigree can be used to estimate cancer risk. This type of calculation uses the probability the individual harbors a genetic variant and variant-specific penetrance data to calculate cancer risk.[1]
In the absence of evidence of a hereditary cancer syndrome, several methods can be utilized to estimate cancer risk. Relative risk data from studies of specific risk factors provide ratios of observed versus expected cancers associated with a given risk factor. However, utilizing relative risk data for individualized risk assessment can have significant limitations: relative risk calculations will differ based on the type of control group and other study-associated biases, and comparability across studies can vary widely.[51] In addition, relative risks are lifetime ratios and do not provide age-specific calculations, nor can the relative risk be multiplied by population risk to provide an individual’s risk estimate.[51,54]
In spite of these limitations, disease-specific cumulative risk estimates are most often employed in clinical settings. These estimates usually provide risk for a given time interval and can be anchored to cumulative risks of other health conditions in a given population (e.g., the 5-year risk by the Gail model).[51,54] Cumulative risk models have limitations that may underestimate or overestimate risk. For example, the Gail model excludes paternal family histories of breast cancer.[50] Furthermore, many of these models were constructed from data derived from predominantly white populations and may have limited validity when used to estimate risk in other ethnicities.[55]
Cumulative risk estimates are best used when evidence of other underlying significant risk factors have been ruled out. Careful evaluation of an individual’s personal health and family history can identify other confounding risk factors that may outweigh a risk estimate derived from a cumulative risk model. For example, a woman with a prior biopsy showing lobular carcinoma in situ (LCIS) whose mother was diagnosed with breast cancer at age 65 years has a greater lifetime risk from her history of LCIS than her cumulative lifetime risk of breast cancer based on one first-degree relative.[56,57] In this circumstance, recommendations for cancer risk management would be based on the risk associated with her LCIS. Unfortunately, there is no reliable method for combining all of an individual’s relevant risk factors for an accurate absolute cancer risk estimate, nor are individual risk factors additive.
In summary, careful ascertainment and review of personal health and cancer family history are essential adjuncts to the use of prior probability models and cancer risk assessment models to assure that critical elements influencing risk calculations are considered.[49] Influencing factors include the following:
A number of investigators are developing health care provider decision support tools such as the Genetic Risk Assessment on the Internet with Decision Support (GRAIDS),[58] but at this time, clinical judgment remains a key component of any prior probability or absolute cancer risk estimation.[49]
Experts recommend offering genetic testing when a risk assessment suggests the presence of an inherited cancer syndrome for which specific genes have been identified. The American Society of Clinical Oncology (ASCO) Policy Statement on Genetic Testing for Cancer Susceptibility proposes that genetic testing be offered when the following conditions apply:[1,2]
Characteristics used in making this determination are discussed in the PDQ summaries on the genetics of specific cancers. Even when individual and family history characteristics indicate a possible inherited cancer syndrome, individuals may elect not to proceed with testing after discussion of potential risks, benefits, and limitations, as discussed below. Conversely, individuals whose pedigrees are incomplete or uninformative due to very small family size, early deaths, or incomplete data on key family members may elect to pursue genetic testing in an attempt to better define their risk status. In these situations, it is particularly important that the pretest counseling fully explore the limitations of the testing process.
ASCO’s 2010 and 2015 policy statements addressed testing for low- to moderate-penetrance genes and direct-to-consumer testing.[1,2]
ASCO’s position is that when a test, regardless of clinical utility, is ordered by a health care professional, the provider is responsible for organizing follow-up care based on the findings. For tests that are ordered by the consumer without health care professional involvement, management decisions are based on the evidence for clinical utility. For tests with accepted clinical utility, follow-up care can be guided by the evidence for cancer risk associated with the genetic test finding. However, in tests ordered by the consumer that have uncertain clinical utility, ASCO recommends that follow-up care consist of education regarding the lack of evidence regarding the test’s clinical utility and that cancer risk management decisions be guided by established cancer risk factors.[1,2]
In 2015, ASCO updated its policy to address the challenges of new technologies in cancer genetics, including multigene (panel) testing for cancer genetic susceptibility, as well as incidental germline findings from somatic mutation profiling.[2] ASCO’s statement expressed support for communicating medically relevant germline findings discovered in the context of somatic mutation profiling.[2]
Genetic education and counseling, including the interpretation of genetic test results, will vary depending on whether a previous attempt at genetic testing has been made (refer to Figure 2). In general, there are two primary circumstances in which genetic testing is performed:
Figure 2. This genetic testing algorithm depicts the multistep process of testing for cancer susceptibility.
Genetic susceptibility testing generally yields the most useful information when a living family member affected with the cancer of concern is tested first to determine whether a genetic basis for the cancer diagnosis can be established. If testing is deferred while follow-up with an affected relative is pending, consider providing interim cancer risk management guidelines to the unaffected proband.[3] Three possible outcomes of testing include the following (refer to Figure 2):
If a documented pathogenic variant (associated with cancer risk) is identified, risks are based on penetrance data for pathogenic variants of that specific gene. In addition, other family members may be tested for the presence or absence of this specific pathogenic variant. If no variant is found in an affected family member, testing is considered uninformative and thus there is no basis for testing unaffected relatives. Failure of the laboratory to detect a pathogenic variant in an affected family member does not rule out an inherited basis for the cancer in that family. Reasons why testing could be uninformative include the following:
Lastly, testing may reveal a VUS. This result means that a genetic variant has been found; however, the extent that this variant increases cancer risk, or whether it is associated with the history of cancer in the family, is uncertain. In this circumstance, some clues as to the significance of the variant can be derived from the following:
Unfortunately, even with this information, there is often insufficient evidence to document the significance of a specific variant, and further clarifying research is required.
If there is no close, living, affected relative to undergo testing, or the living affected relative declines testing, other options may be discussed with the patient and the testing laboratory. In rare instances, if proper authorization is secured from the family, testing the stored tissue of a deceased relative may be considered. However, genetic tests done on stored tissue are technically difficult and may not yield a definitive result. Therefore, testing an unaffected person without prior testing of an affected family member may be performed. In these instances, counseling includes discussing that a negative test result does not rule out the presence of a cancer susceptibility gene in the family or in the patient and may be uninformative.
Genetic susceptibility testing for a documented pathogenic variant in the family can be very informative and will yield one of the following two results (refer to Figure 2):
If the familial pathogenic variant is detected in a family member, their cancer risks are based on penetrance data for pathogenic variants in that specific gene. If the documented pathogenic variant is not found in a family member, the risk of cancer in that individual is equivalent to cancer risk in the general population. However, other risk factors and family history from the side of the family not associated with the documented pathogenic variant may increase the cancer risk above the general population levels.
In summary, genetic education and counseling includes identifying the most informative person in the family to test, which may be an affected family member rather than the individual seeking genetic services. In addition, counseling includes a discussion of the limitations of the test, all possible test outcomes, and the consequences of identifying a VUS.[4]
Insurance coverage varies for cancer susceptibility testing, including multigene (panel) testing. In general, most individuals who meet specific criteria (e.g., National Comprehensive Cancer Network [NCCN] guidelines for BRCA1/BRCA2 or Lynch syndrome testing) are able to obtain insurance coverage for multigene testing.[5] Of note, some insurance companies have contracts with specific laboratories through which testing must be ordered.
The Affordable Care Act (ACA) requires that private insurers cover—with no out-of-pocket costs to the insured—genetic counseling and BRCA1/BRCA2 testing for unaffected women meeting United States Preventive Services Task Force guidelines.[6,7] Importantly, under ACA guidelines, women with a prior cancer diagnosis are not covered. The ACA does not stipulate that follow-up care based on genetic test results be covered (e.g., risk-reducing surgeries). However, some insurance companies require that pretest genetic counseling be performed by a credentialed genetics provider before testing is authorized. Before testing is ordered, it is important to verify costs and insurance coverage, including for Medicaid and Medicare patients. Medicare does not cover genetic testing if the patient has not had a cancer diagnosis associated with the pathogenic variants for which testing is ordered. In addition, unaffected individuals with Medicare are not covered for testing, even if they are tested for only a known familial pathogenic variant. Further, Medicare does not cover genetic counseling as a separately billable service.[8] For individuals without insurance coverage and the underinsured, some laboratories offer low-cost options or have financial assistance programs.
There is a risk of carriers passing on cancer-associated pathogenic variants to offspring. When an individual tests positive for one pathogenic variant in a cancer susceptibility gene, counseling about reproductive implications addresses not only the risks associated with autosomal dominant inheritance but also the potential risks of having a child with two pathogenic variants in the same gene (biallelic) that could result in a severe condition.
Assisted reproductive technology can be used for preimplantation genetic testing (PGT) and for prenatal cancer predisposition genetic testing using chorionic villus sampling and amniocentesis.[9–11] For individuals with autosomal dominant cancer syndromes (e.g., those associated with APC, BRCA1/BRCA2, PTEN, or TP53 pathogenic variants), reproductive options exist for prenatal testing and PGT to detect offspring with one copy of the pathogenic variant (heterozygotes).
In some cases (e.g., carriers of germline pathogenic variants in ATM, BLM), assessing an individual’s partner’s risk for carrying a pathogenic variant associated with a dominant or recessive syndrome (i.e., his or her personal and family history and ethnicity) is indicated. In the unlikely event that both parents are heterozygous for specific pathogenic variants, there is a 25% risk that a child will be homozygous and could have a severe phenotype. In light of this information, couples may consider PGT or prenatal testing.
A proposed analytic framework for counseling carriers about reproduction options includes consideration of the following issues:[10]
In a study of 320 patients with different hereditary cancer syndromes, most were unaware of PGT; however, the majority expressed interest in learning more about the availability of PGT.[14] Patients also preferred having a discussion about PGT with their genetic counselor or primary physician. Disease-specific factors (e.g., severity of the hereditary condition, quality of life, and medical interventions) and individual factors (e.g., gender, childbearing status, and religious beliefs) affected patient attitudes about PGT.
Genetic testing is highly specialized. There are also multiple molecular testing methods available, each with its own indications, costs, strengths, and weaknesses. Depending on the method employed and the extent of the analysis, different tests for the same gene will have varying levels of sensitivity and specificity. Even assuming high analytic validity, genetic heterogeneity makes test selection challenging. A number of different genetic syndromes may underlie the development of a particular cancer type. For example, hereditary colorectal cancer may be due to familial adenomatous polyposis (FAP), Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, or other syndromes. Each of these has a different genetic basis. In addition, different genes may be responsible for the same condition (e.g., Lynch syndrome can be caused by pathogenic variants in one of several mismatch repair [MMR] genes).
In some genes, the same pathogenic variant has been found in multiple, apparently unrelated families. This observation is consistent with a founder effect, wherein a pathogenic variant identified in a contemporary population can be traced back to a small group of founders isolated by geographic, cultural, or other factors. For example, two specific BRCA1 pathogenic variants (68_69delAG and 5266dup, also known in the literature as 185delAG and 5382insC) and one BRCA2 pathogenic variant (5946delT, also known as 6174delT) have been reported to be common in Ashkenazi Jews. Other genes also have reported founder pathogenic variants. The presence of founder pathogenic variants has practical implications for genetic testing. Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without limitations. For example, approximately 15% of BRCA1 and BRCA2 pathogenic variants that occur among Ashkenazim are nonfounder pathogenic variants.[15] Also, for genes in which large genome rearrangements are common in the founder population, ordering additional testing using different techniques may be needed.
Allelic heterogeneity (i.e., different variants within the same gene) can confer different risks or be associated with a different phenotype. For example, though the general rule is that adenomatous polyposis coli (APC) pathogenic variants are associated with hundreds or thousands of colonic polyps and colon cancer of the classical FAP syndrome, some APC pathogenic variants cause a milder clinical picture, with fewer polyps and lower colorectal cancer risk.[16,17] In addition, other disorders may be part of the FAP spectrum. Pathogenic variants in a certain portion of the APC gene also predispose to retinal changes, for example, when pathogenic variants in a different region of APC predispose to desmoid tumors.
In light of the heterogeneity in presentation and potential overlap in phenotypes among the various hereditary cancer syndromes, the selection of the appropriate genetic test for a given individual requires knowledge of genetic syndromes, molecular diagnostic methods used for identifying pathogenic variants, correlation between clinical and molecular findings, and access to information about rapidly changing testing options. These issues are addressed in detail in PDQ summaries on the genetics of specific cancers. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; Genetics of Endocrine and Neuroendocrine Neoplasias; Genetics of Skin Cancer; Genetics of Renal Cell Carcinoma; and Genetics of Prostate Cancer for more information.)
Next-generation sequencing (NGS) and the removal of most patent barriers to diagnostic DNA sequencing [18] have resulted in the availability of multigene testing, which can simultaneously test more than 50 genes for pathogenic variants, often at costs comparable to single-gene testing. These multigene panels can include genes with pathogenic variants that are associated with high risks of cancer and genes that confer moderate and uncertain risks. The multigene panels can be limited to specific cancer types (e.g., breast, ovarian, colon) or can include many cancer types. This type of testing has both advantages and disadvantages, and much of the information presented in this section is not based on empirical data but rather on commentaries.
ASCO has stressed the importance of genetic counseling to ensure patients are adequately informed about the implications of this type of testing and recommends that tests be ordered by cancer genetic professionals.[2,19] Yet, the use of multigene testing requires modification of traditional approaches to genetic counseling.[20,21] Optimal evidence-based counseling strategies have not yet been established. Unlike in-person, single-gene pretest genetic counseling models, these approaches have not been examined for outcomes of counseling such as comprehension, satisfaction, psychosocial outcomes, and testing uptake. Table 2 summarizes recommendations from ASCO on elements of pretest genetic counseling and informed consent for germline cancer genetic testing.[2]
| Topic | Traditional Germline Cancer Genetic Testing | Multigene Panel Germline Cancer Genetic Testing |
|---|---|---|
| aAdapted from Robson et al.[2] | ||
| Gene Information | Specific gene(s) or gene variant(s) being tested. | Review of specific genes included in a multigene panel may need to be batched because it is not feasible to individually cover each gene. |
| Risks associated with the gene(s) or gene variants(s) and implications for health care. | Describe high-penetrance gene(s) and/or syndromes included in the multigene panel (i.e., hereditary breast-ovarian syndrome, Lynch syndrome, hereditary diffuse gastric cancer, Li-Fraumeni syndrome), possible detection based on personal and family history and general implications for health care. | |
| Describe generally genes of uncertain clinical utility. | ||
| Possible Test Outcomes | • Pathogenic variant detected. | |
| • No variant detected. | ||
| • Variant of uncertain significance (VUS) detected. | ||
| Variant in a gene for which there is: | ||
| • Limited evidence regarding penetrance. | ||
| • Discordant findings (pathogenic variant identified in a gene that is inconsistent with the patient's personal and/or family history). | ||
| Increased rate of VUS. | ||
| Risks, Benefits, and Limitations of Genetic Testing | Psychosocial implications of test results. | |
| Confidentiality considerations, including privacy, data security, and placement of results (i.e., electronic health record). | ||
| Use of DNA sample(s) for future research. | ||
| Employment and insurance discrimination risks and protections. | ||
| Costs involved in testing and scope of insurance coverage if applicable. | ||
| Whether the genetic health care professional is employed by the testing company. | ||
| Implications of Genetic Testing for Family Members | Pattern of variant transmission and risks of inheritance in children and other family members. | |
| Importance of sharing test results with family members. | ||
| Possible reproductive implications associated with pathogenic variants in genes associated with recessive conditions (i.e., ATM, Fanconi anemia [BRCA2, PALB2], NBN, BLM). | ||
| Use of Genetic Test Results | Implications of genetic test results on health care. | |
The range of results from NGS multigene panels is emerging in both data from clinical and laboratory series. Several of the studies are collaborations between the two. There are several important caveats about the research that has been conducted so far with regard to multigene testing:
In high-risk individuals who meet criteria for hereditary cancer genetic testing but in whom no pathogenic variant was identified from single-gene testing, panel testing may identify other clinically actionable variants.[27,28] For example, the additional yield of multigene testing in individuals in whom a BRCA1/BRCA2 pathogenic variant was not detected currently seems to be approximately 4%.[26,29,30] The most common non-BRCA pathogenic variants found are in CHEK2, ATM, and PALB2.[26,29–31] In some cases, the identification of pathogenic variants from panel testing resulted in additional recommendations for screening and risk reduction beyond what would have been indicated based on family history alone.[30,32–34]
Selected reports from 2014 to 2018, which included 1,000 to 10,000 tested individuals, showed variation in pathogenic variant and VUS rates.[23,24,26,30,35–38] Pathogenic variant rates ranged from 7% to 14%; VUS rates ranged from 19% to 41% and increased with the number of genes included on the panel, but decreased in the later studies, likely because of larger data pools and refinements in variant interpretation. Additionally, VUS rates were higher in non-White individuals, likely because of the limited availability of test result data needed for accurate determination of risk.[38]
A large study published by a commercial laboratory included more than 252,000 individuals who were tested with a 25-gene panel between 2013 and 2016.[39] The study reported an overall pathogenic variant rate of 6.7% (9.8% in affected individuals and 4.7% in unaffected individuals), with an overall VUS rate of 30%. The study population was 97% female, had no prior cancer genetic testing, and 93% met NCCN criteria for hereditary breast and ovarian cancer (HBOC) or Lynch syndrome testing. It was noted that half of the pathogenic variants found for HBOC or Lynch syndrome were not in the expected genes associated with these syndromes (BRCA1, BRCA2, MLH1, MSH2, MSH6, and PMS2).
Results from multigene tests have several possible outcomes, including the following:[19]
Results can also reveal more than one finding given that multiple genes are being tested simultaneously and the elevated rate of VUS.[21] There has been no assessment of outcomes of multigene tests such as comprehension, psychosocial outcomes, and uptake of cancer risk management options.
Utilizing multigene panels can be complex but may offer advantages over sequential testing strategies. First, in some types of cancer, several genes can be associated with specific phenotypes; therefore, testing for all genes associated with a given phenotype can save both time and money.[40] Additionally, multigene testing may help identify the genetic basis for cancer in families in whom the differential diagnosis includes multiple syndromes or when the family history does not meet standard criteria for a single cancer syndrome.[21,40] (Refer to the Analysis of the family history section of this summary for a list of factors that may make a family history difficult to interpret.)
However, there can be challenges to employing this testing approach. Clinical laboratories now offer a varying array of clinical cancer susceptibility gene panels.[41,42] Multigene panels continue to evolve, and the genes included on the panels can change. Other challenges of interpreting multigene test results include higher rates of VUS than with single-gene testing (the rate of VUS increases with the number of genes tested),[24] higher rates of VUS in some minority populations,[32,43] and the detection of variants in genes associated with uncertain cancer risks.
In addition to these primary challenges, providers deciding the optimal testing strategy may also consider the following: the overall expense and out-of-pocket expense to the patient; insurance reimbursement; time frame to complete the test; ease of laboratory use for the clinician ordering testing; the probability of identifying a VUS and management of those findings, such as the reclassification process and provision of supplemental data regarding the variant; technical differences, such as the presence of a deletion/duplication assay; patient preference; and clinical history.[2,40,41,44]
Overall, there is insufficient evidence to determine superiority of multigene testing over phenotype-guided testing or sequential gene testing.[19] As a consequence, practice guidelines for optimal clinical use of multigene tests continue to evolve.[2,45] The NCCN and ASCO guidelines suggest that efficiencies may be gained by using multigene testing when there is more than one cancer syndrome or gene on the differential diagnosis list.[2,45] Additionally, NCCN states that there may be a role for multigene testing when a patient has a personal or family history that is consistent with an inherited susceptibility but single-gene testing has not identified a pathogenic variant.[45]
Another important consideration is that multigene tests may include genes in which pathogenic variants are associated with moderate or uncertain penetrance. Management of individuals with pathogenic variants in such genes can present additional challenges, particularly when expert consensus or evidence-based recommendations are not available. (Refer to Figure 1 in the Cancer Genetics Overview PDQ summary for information about moderate and low penetrance.) Moreover, there may be limited or no evidence to support changes to medical management based on the level of risk or uncertain risk; however, management may still be affected by family history.[1,2] A framework for clinical management incorporates emerging data on age-specific, lifetime, and absolute cancer risks conferred by pathogenic variants in several moderate-risk genes.[46] (Refer to the Penetrance of Inherited Susceptibility to Hereditary Breast and/or Gynecologic Cancers section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about this framework.)
Government regulation of genetic tests to date remains extremely limited in terms of both analytic and clinical validity with little interagency coordination.[47] The Centers for Medicare & Medicaid Services, using the Clinical Laboratory Improvement Act (CLIA), regulates all clinical human laboratory testing performed in the United States for the purposes of generating diagnostic or other health information. CLIA regulations address personnel qualifications, laboratory quality assurance standards, and documentation and validation of tests and procedures.[48] For laboratory tests themselves, CLIA categorizes tests based on the level of complexity into waived tests, moderate complexity, or high complexity. Genetic tests are considered high complexity, which indicates that a high degree of knowledge and skill is required to perform or interpret the test. Laboratories conducting high complexity tests must undergo proficiency testing at specified intervals, which consists of an external review of the laboratory’s ability to accurately perform and interpret the test.[47,49] However, a specialty area specific for molecular and biologic genetic tests has yet to be established; therefore, specific proficiency testing of genetic testing laboratories is not required by CLIA.[47]
In regard to analytic validity, genetic tests fall into two primary categories; test kits and laboratory-developed tests (previously called home brews). Test kits are manufactured for use in laboratories performing the test and include all the reagents necessary to complete the analysis, instructions, performance outcomes, and details about which genetic variants can be detected. The U.S. Food and Drug Administration (FDA) regulates test kits as medical devices; however, despite more than 1,000 available genetic tests, there are fewer than ten FDA-approved test kits.[49] Laboratory-developed tests are performed in a laboratory that assembles its own testing materials in-house;[49] this category represents the most common form of genetic testing. Laboratory-developed tests are subject to the least amount of oversight, as neither CLIA nor the FDA evaluate the laboratories’ proficiency in performing the test or clinical validity relative to the accuracy of the test to predict a clinical outcome.[47,49] The FDA does regulate manufactured analyte-specific reagents (ASRs) as medical devices. These small molecules are used to conduct laboratory-developed tests but can also be made by the laboratory. ASRs made in the laboratory are not subject to FDA oversight. For laboratory-developed tests utilizing manufactured commercially available ASRs, the FDA requires that the test be ordered by a health professional or other individual authorized to order the test by state law. However, this regulation does not distinguish between health providers caring for the patient or health providers who work for the laboratory offering the test.[49]
In addition to the regulation of classical clinical genetic tests is the regulatory oversight of research genetic testing. Laboratories performing genetic testing on a research basis are exempt from CLIA oversight if the laboratory does not report patient-specific results for the diagnosis, prevention, or treatment of any disease or impairment or the assessment of the health of individual patients.[47] However, there are anecdotal reports of research laboratories providing test results for clinical purposes with the caveat that the laboratory recommends that testing be repeated in a clinical CLIA-approved laboratory. In addition, there is no established mechanism that determines when a test has sufficient analytic and clinical validity to be offered clinically.[49] Currently, the decision to offer a genetic test clinically is at the discretion of the laboratory director.
Evidence regarding the implications of this narrow regulatory oversight of genetic tests is limited and consists predominantly of laboratory director responses to quality assurance surveys. A survey of 133 laboratory directors performing genetic tests found that 88% of laboratories employed one or more American Board of Medical Genetics (ABMG)-certified or ABMG-eligible professional geneticists, and 23% had an affiliation with at least one doctoral-prepared geneticist. Eight percent of laboratories did not employ and were not affiliated with doctoral-level genetics professionals. Laboratory-developed tests were performed in 70% of laboratories. Sixty-three percent of laboratories provided an interpretation of the test result as part of the test report.[50] Another survey of 190 laboratory directors found that 97% were CLIA-certified for high complexity testing. Sixteen percent of laboratories reported no specialty area certification; those without specialty certification represented laboratories with the most volume of tests performed and offered the most extensive test selection.[47] Of laboratories with specialty certification, not all had certification relevant to genetic tests, with 48% reporting pathology certification, 46% chemistry certification, and 41% clinical cytogenetics certification. Sixteen percent of directors reported participation in no formal external proficiency testing program, although 77% performed some informal proficiency testing when a formal external proficiency testing program was not available.
The most frequent reason cited for lack of proficiency testing participation was lack of available proficiency testing programs. Laboratory directors estimated that in the past 2 years 37% issued three or fewer incorrect reports, and 35% issued at least four incorrect reports. Analytic errors such as faulty reagent, equipment failure, or human error, increased 40% with each decrease in level of proficiency training completed.[47] An international genetic testing laboratory director survey involving 18 countries found that 64% of the 827 laboratories that responded accepted samples from outside their country.[51] Similar to the U.S. study, 74% reported participation in some form of proficiency testing. Fifty-three percent of the laboratories required a copy of the consent to perform the test, and 72% of laboratories retained specimens indefinitely that were submitted for testing.[51]
The U.S. Department of Health and Human Services Secretary’s Advisory Committee on Genetics, Health, and Society has published a detailed report regarding the adequacy and transparency of the current oversight system for genetic testing in the United States.[52] The Committee identified gaps in the following areas:
In October 2014, the FDA posted the notification regarding its plans to develop draft guidance on the regulation of laboratory-developed tests.[53] Draft guidance documents outlining the framework for regulatory oversight for the industry and clinical laboratories were published later in 2014 for public review and comment. Given the potential of such regulatory action to affect the wide spectrum of genetic tests in clinical practice, proposed draft guidelines have been discussed and reviewed by a number of professional associations, eliciting policy statements and analyses from various professional associations, including the American Society of Human Genetics (ASHG)Exit Disclaimer and the Association for Molecular PathologyExit Disclaimer. The issue of FDA oversight of laboratory-developed tests remains under consideration.
Most genetic testing for cancer and other health risks is offered by health care providers on the basis of a patient’s personal history, family history, or ethnicity. Increasingly, however, individuals can order genetic testing through DTC companies without the input of health care providers. DTC tests may provide information about ancestry, paternity, propensity toward certain physical traits, risk of adverse drug reactions, and disease risks.
In 2015, the FDA provided clearanceExit Disclaimer for a large DTC company (23andMe) to market carrier screening for Bloom syndrome, which is associated with increased cancer risks in homozygotes as well as other phenotypic features. Subsequently, DTC carrier testing for several conditions became available. In 2017, the FDA allowed 23andMe to market DTC tests for ten diseases or conditions including late-onset Alzheimer disease, Parkinson disease, and hereditary thrombophilia.[54] It is important to note that the carrier and health tests authorized for marketing by the FDA are performed by genotyping, which means that only specific nucleotides or bases are targeted for analysis; sequencing is not performed.[55] Thus, while the false-positive or false-negative rate for a specific genotype is very low (i.e., analytic validity is high), other pathogenic variants are not analyzed, nor is the entire sequence of the gene. Thus, the false-negative rate due to untested pathogenic variants as well as other gene abnormalities is high.
In March 2018, the FDA authorized 23andMe to market DTC testing for three founder pathogenic variants in the BRCA1 and BRCA2 genes that are common in individuals of Ashkenazi Jewish descent.[56] These three variants are rare among high-risk individuals who are not of this ethnicity and in the general population of non-Jewish individuals. However, Jewish individuals whose family history is suggestive of hereditary breast/ovarian cancer who test negative for these three variants warrant additional testing.
It is crucial for individuals who obtain a BRCA1/BRCA2 (or any health-related) positive result from DTC testing to pursue clinical confirmation of such a result. Clinical confirmation entails repeating the test in a CLIA-certified laboratory, as well as individual review and verification of the result by laboratory personnel.
A potential advantage of DTC testing of these three BRCA1/BRCA2 pathogenic variants is that it will identify individuals who would not have been otherwise aware of their increased risk of associated cancers, for example if they have no personal or family history of breast, ovarian, or prostate cancer. This is one of the main arguments for population-based screening for BRCA1/BRCA2 pathogenic variants. (Refer to the Population screening section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)
However, a negative result does not rule out other hereditary factors or account for other clinical indicators, genetic and nongenetic, of increased cancer risk. Thus, for most individuals who test negative for the three BRCA1/BRCA2 variants, the results do not provide reassurance about their cancer risks. For high-risk individuals in particular (i.e., those with a history suggestive of hereditary breast/ovarian cancer) a negative result from this limited testing is incomplete, given that it does not assess the presence or absence of other pathogenic variants in BRCA1/BRCA2 or in many other cancer-associated genes.
Consumer-directed clinical testing is used to describe a hybrid approach to genetic testing, whereupon clinical–grade genetic testing can be initiated and selected by a consumer; however, ordering of the test by an authorized provider (e.g., primary care physician, nurse practitioner, or genetic counselor) is required.[57] The test ordering may be coordinated by the testing company. Genetic counseling may also be offered by the laboratory to explain the results.
With respect to cancer genetic testing, there are clinical, CLIA-certified laboratories that offer multigene (panel) tests as a consumer-directed service. Things to consider when genetic testing is ordered this way include:
Multigene (panel) tests may not include all high- to moderate-risk genes in the differential, or newer/preliminary evidence genes.
This is an important question to ask before testing is performed.
Particularly for individuals who meet criteria for testing, insurance may cover the cost, whereas the consumer is responsible for the costs of consumer-directed testing. However, for individuals who do not meet criteria for testing and/or for whom insurance will not pay, the cost of consumer-directed testing may not be higher than out-of-pocket costs when ordered after pretest genetic counseling.
Some insurance companies require patients to have pretest genetic counseling by a credentialed genetics provider (and to meet specific eligibility criteria) in order for the testing to be covered. Consumer-directed testing thus eliminates the need for this requirement.
In the past, several DTC companies offered only SNV-based testing to generate information about health risks, including risks of cancer. Selection of SNVs may be based on data from genome-wide association studies (GWAS); however, there is no validated algorithm outlining how to generate cancer risk estimates from different SNVs, which individually are generally associated with modestly increased disease risks (usually conferring odds ratios <2.0) or modestly decreased disease risks.[58] (Refer to the GWAS section in the PDQ summary on Cancer Genetics Overview for more information.) As a result, predicted disease risks from different DTC companies may yield different results. For example, a sample comparison of SNV-based risk prediction from two different companies for four different cancers yielded relative risks of 0.64 to 1.42 (excluding the three Ashkenazi BRCA1/BRCA2 founder pathogenic variants).[59] In addition, because commercial companies use different panels of SNVs, there is seldom concordance about the predicted risks for common diseases, and such risk estimates have not been prospectively validated.[60,61]
Another area of investigation is whether predicted disease risks from SNV testing are consistent with family history–based assessments. Studies using data from one commercial personal genomic testing company revealed that there was generally poor concordance between the SNV and family history risk assessment for common cancers such as breast, prostate, and colon.[62–64] Importantly, one of these studies highlighted that the majority of individuals with family histories suggestive of hereditary breast/ovarian cancer or Lynch syndrome received SNV results yielding lifetime cancer risks that were average or below average.[62]
Studies have begun to examine whether SNV testing could be used together with other established risk factors to assess the likelihood of developing cancer. For example, adding SNV data to validated breast cancer prediction tools such as those included in the National Cancer Institute’s Breast Cancer Risk Assessment Tool (based on the Gail model) [65] may improve the accuracy of risk assessment.[66,67] However, this approach is not currently FDA-approved.
These findings underscore that SNV testing has not been validated as an accurate risk assessment tool and does not replace the collection, integration, and interpretation of personal and family history risk factor information by qualified health care professionals.
Increasingly, DTC testing companies offer whole-genome sequencing (WGS) or whole-exome sequencing (WES), including SNV data. (Refer to the Clinical Sequencing section in the PDQ summary on Cancer Genetics Overview for a description of WGS and WES.) In addition, consumers who submit their DNA to a DTC lab may have access to their raw sequence data and may consult with other companies, websites, and open-access databases for interpretation.[68,69] However, these data must be interpreted with caution. A clinical lab found that 40% of variants reported in DTC raw data were false positives (i.e., low analytic validity because the identified variant was not present).[70] In addition, several variants that were designated as “increased risk” in the raw data were classified as benign by clinical laboratories and public databases.[70] Given the potential for misinterpretation, which may lead to unnecessary medical procedures or testing, these findings underscore the importance of clinical confirmation of all potentially medically actionable gene variants identified by DTC testing.
Some factors to consider when determining the accuracy and utility of sequence data for cancer (or other disease) risk assessment include the sequencing depth of the genes of interest, whether large rearrangements or gene deletions would be detected, and whether or how positive results are confirmed (e.g., through Sanger sequencing). For example, if sequencing depth is low or rare variants cannot be detected, then there is a concern about false-negative results. There is also a risk that sequence changes will be erroneously labeled as pathogenic when confirmatory testing or different interpretative approaches would determine that the variant identified is benign (false positive). When WES or WGS is performed, VUS are also likely to be identified,[71] and DTC companies have varying protocols for classification, which may or may not be consistent with national guidelines (e.g., refer to [72]). In addition, as evidence evolves and variants are reclassified, consumers need to be aware of the process the DTC lab has, if any, for updating information and re-contacting consumers with revised interpretations.
There may be potential benefits associated with DTC testing. DTC marketing and provision of genetic tests may promote patient autonomy.[59] Individuals may develop an increased awareness of the importance of family history, the relationship between risk and family history, the role of genetics in disease, and a better understanding of the value of genetic counseling.[73] Although results of SNV-based DTC testing appear to motivate some individuals to seek the advice of their doctor, make lifestyle changes, and pursue screening tests,[74–77] short-term modest effects on risk perception after notification of an elevated risk (e.g., for cancer) may not significantly alter lifestyle or cancer screening behaviors.[78,79] Further, psychological distress has not been widely reported among consumers who have undergone DTC testing for a variety of conditions.[76] However, little is known about how individuals respond after learning that they carry pathogenic variants in high-risk genes such as BRCA1/BRCA2 when testing is performed within a DTC context and without traditional forms of pre- and posttest genetic education and counseling.
Given the complexity of genomic testing, several professional organizations have released position statements about DTC genetic testing. For example, in 2010, ASCO published a position statement outlining several considerations related to DTC cancer genomic tests, including those mentioned above.[1] They endorsed pre- and posttest genetic counseling and informed consent by qualified health care professionals. ASCO’s 2015 position statement on genetic and genomic testing for cancer susceptibility reinforces the importance of provider education given the complexity of genomic testing and interpretation and discusses their recommendations for regulatory review of genomic tests, including those offered by DTC companies.[2]
In 2016, a statement by the American College of Medical Genetics and Genomics about DTC genetic testing similarly endorsed the involvement of qualified genetics professionals in the processes of test ordering and interpretation.[80] The statement also emphasized the need to incorporate established methods of risk assessment into disease risk prediction (such as personal and family medical history information) and stressed that consumers need to be informed about the potential limitations and risks associated with DTC testing.
Informed consent can enhance preparedness for testing, including careful weighing of benefits and limitations of testing, minimization of adverse psychosocial outcomes, appropriate use of medical options, and a strengthened provider-patient relationship based on honesty, support, and trust.
Consensus exists among experts that a process of informed consent should be an integral part of the pretest counseling process.[81] This view is driven by several ethical dilemmas that can arise in genetic susceptibility testing. The most commonly cited concern is the possibility of insurance or employment discrimination if a test result, or even the fact that an individual has sought or is seeking testing, is disclosed. In 2008, Congress passed the Genetic Information Nondiscrimination Act of 2008 (GINA). This federal law provides protections related to health insurance and employment discrimination based on genetic information. However, GINA does not cover life, disability, or long-term-care insurance discrimination.[82] (Refer to the GINA section of this summary for more information.) A related issue involves stigmatization that may occur when an individual who may never develop the condition in question, or may not do so for decades, receives genetic information and is labeled or labels himself or herself as ill. Finally, in the case of genetic testing, medical information given to one individual has immediate implications for biologic relatives. These implications include not only the medical risks but also disruptions in familial relationships. The possibility for coercion exists when one family member wants to be tested but, to do so optimally, must first obtain genetic material or information from other family members.
Inclusion of an informed consent process in counseling can facilitate patient autonomy.[83] It may also reduce the potential for misunderstanding between patient and provider. Many clinical programs provide opportunities for individuals to review their informed consent during the genetic testing and counseling process. Initial informed consent provides a verbal and/or written overview of the process.
Some programs use a second informed consent process prior to disclosure to the individual of his or her genetic test results. This process allows for the possibility that a person may change his or her mind about receiving test results. After the test result has been disclosed, a third informed consent discussion often occurs. This discussion concerns issues regarding sharing the genetic test result with health providers and/or interested family members, currently or in the future. Obtaining written permission to provide the test result to others in the family who are at risk can avoid vexing problems in the future should the individual not be available to release his or her results.
Major elements of an informed consent discussion are highlighted in the preceding discussion. The critical elements, as described in the literature,[1,2,84,85] include the following:
All individuals considering genetic testing should be informed that they have several options even after the genetic testing has been completed. They may decide to receive the results at the posttest meeting, delay result notification, or less commonly, not receive the results of testing. They should be informed that their interest in receiving results will be addressed at the beginning of the posttest meeting and that time will be available to review their concerns and thoughts on notification. It is important that individuals receive this information during the pretest counseling to ensure added comfort with the decision to decline or defer result notification even when test results become available.
Genetic testing for pathogenic variants in cancer susceptibility genes in children is particularly complex. While both parents [86] and providers [87] may request or recommend testing for minor children, many experts recommend that unless there is evidence that the test result will influence the medical management of the child or adolescent, genetic testing should be deferred until legal adulthood (age 18 y or older) because of concerns about autonomy, potential discrimination, and possible psychosocial effects.[88–90] A number of cancer syndromes include childhood disease risk, such as retinoblastoma, multiple endocrine neoplasia (MEN) types 1 and 2 (MEN1 and MEN2), neurofibromatosis types 1 and 2 (NF1 and NF2), Beckwith–Wiedemann syndrome, Fanconi anemia, FAP, and Von Hippel-Lindau disease (VHL).[91,92] As a consequence, decisions about genetic testing in children are made in the context of a specific gene in which a pathogenic variant is suspected. The ASCO statement on genetic testing for cancer susceptibility maintains that the decision to consider offering childhood genetic testing should take into account not only the risk of childhood malignancy but also the evidence associated with risk reduction interventions for that disorder.[1] Specifically, ASCO recommends that:
Special considerations are required when genetic counseling and testing for pathogenic variants in cancer susceptibility genes are considered in children. The first issue is the age of the child. Young children, especially those younger than 10 years, may not be involved or may have limited involvement in the decision to be tested, and some may not participate in the genetic counseling process. In these cases, the child’s parents or other legal surrogate will be involved in the genetic counseling and will ultimately be responsible for making the decision to proceed with testing.[1,93] Counseling under these circumstances incorporates a discussion of how test results will be shared with the child when he or she is older.[1] Children aged 10 to 17 years may have more involvement in the decision-making process.[94] In a qualitative study of parents and children aged 10 to 17 years assessing decision making for genetic research participation, older, more mature children and families with open communication styles were more likely to have joint decision making. The majority of children in this study felt that they should have the right to make the final decision for genetic research participation, although many would seek input from their parents.[94] While this study is specific to genetic research participation, the findings allude to the importance children aged 10 to 17 years place on personal decision making regarding factors that impact them. Unfortunately cognitive and psychosocial development may not consistently correlate with the age of the child.[93] Therefore, careful assessment of the child’s developmental stage may help in the genetic counseling and testing process to facilitate parent and child adaptation to the test results. Another complicating factor includes potential risks for discrimination. (Refer to the Employment and Insurance Discrimination section in the Ethical, Legal, and Social Implications section of this summary for more information.)
The consequences of genetic testing in children have been reviewed.[93] In contrast to observations in adults, young children in particular are vulnerable to changes in parent and child bonding based on test results. Genetic testing could interfere with the development of self-concept and self-esteem. Children may also be at risk of developing feelings of survivor guilt or heightened anxiety. All children are especially susceptible to not understanding the testing, results, or implications for their health. As children mature, they begin to have decreased dependency on their parents while developing their personal identity. This can be altered in the setting of a serious health condition or an inherited disorder. Older children are beginning to mature physically and develop intimate relationships while also changing their idealized view of their parents. All of this can be influenced by the results of a genetic test.[93] In its recommendations for genetic testing in asymptomatic minors, the European Society of Human Genetics emphasizes that parents have a responsibility to inform their children about their genetic risk and to communicate this information in a way that is tailored to the child’s age and developmental level.[95,96]
In summary, the decision to proceed with testing in children is based on the use of the test for medical decision making for the child, the ability to interpret the test, and evidence that changes in medical decision making in childhood can positively impact health outcomes. Deferral of genetic testing is suggested when the risk of childhood malignancy is low or absent and/or there is no evidence that interventions can reduce risk.[1] When offering genetic testing in childhood, consideration of the child’s developmental stage is used to help determine his or her involvement in the testing decision and who has legal authority to provide consent. In addition, careful attention to intrafamilial issues and potential psychosocial consequences of testing in children can enable the provider to deliver support that facilitates adaptation to the test result. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; and Genetics of Endocrine and Neuroendocrine Neoplasias for more information about psychosocial research in children being tested for specific cancer susceptibility gene pathogenic variants.)
Genetic counseling and testing requires special considerations when used in vulnerable populations. In 1995, the American Society of Human Genetics published a position statement on the ethical, legal, and psychosocial implications of genetic testing in children and adolescents as a vulnerable population.[89] However, vulnerable populations encompass more than just children. Federal policy applicable to research involving human subjects, 45 CFR Code of Federal Regulations part 46 Protection Of Human Subjects, considers the following groups as potentially vulnerable populations: prisoners, traumatized and comatose patients, terminally ill patients, elderly/aged persons who are cognitively impaired and/or institutionalized, minorities, students, employees, and individuals from outside the United States. Specific to genetic testing, the International Society of Nurses in GeneticsExit Disclaimer further expanded the definition of vulnerable populations to also include individuals with hearing and language deficits or conditions limiting communication (for example, language differences and concerns with reliable translation), cognitive impairment, psychiatric disturbances, clients undergoing stress due to a family situation, those without financial resources, clients with acute or chronic illness and in end-of-life, and those in whom medication may impair reasoning.
Genetic counseling and testing in vulnerable populations raises special considerations. The aim of genetic counseling is to help people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease, which in part involves the meaningful exchange of factual information.[97] In a vulnerable population, health care providers need to be sensitive to factors that can impact the ability of the individual to comprehend the information. In particular, in circumstances of cognitive impairment or intellectual disability, special attention is paid to whether the individual’s legally authorized representative should be involved in the counseling, informed consent, and testing process.
Providers need to assess all patients for their ability to make an uncoerced, autonomous, informed decision prior to proceeding with genetic testing. Populations that do not seem vulnerable (e.g., legally adult college students) may actually be deemed vulnerable because of undue coercion for testing by their parents or the threat of withholding financial support by their parents based on a testing decision inconsistent with the parent’s wishes. Alteration of the genetic counseling and testing process may be necessary depending on the situation, such as counseling and testing in terminally ill individuals who opt for testing for the benefit of their children, but given their impending death, results may have no impact on their own health care or may not be available before their death. In summary, genetic counseling and testing requires that the health care provider assess all individuals for any evidence of vulnerability, and if present, be sensitive to those issues, modify genetic counseling based on the specific circumstances, and avoid causing additional harm.
The complexity of genetic testing for cancer susceptibility has led experts to suggest that careful, in-depth counseling should precede any decision about the use of testing, in keeping with the accepted principles for the use of genetic testing.[98]
Qualitative and quantitative research studies indicate that families hold a variety of beliefs about the inheritance of characteristics within families; some of these beliefs are congruent with current scientific understanding, whereas others are not.[99–101] These beliefs may be influenced by education, personal and family experiences, and cultural background. Because behavior is likely to be influenced by these beliefs, the usefulness of genetic information may depend on recognizing and addressing the individual’s preexisting cognitions. This process begins with initial discussion and continues throughout the genetic counseling process.
An accurate assessment of psychosocial functioning and emotional factors related to testing motivation and potential impact and utilization is an important part of pretest counseling.[102–106] Generally, a provider inquires about a person’s emotional response to the family history of cancer and also about a person’s response to his or her own risk of developing cancer. People have various coping strategies for dealing with stressful circumstances such as genetic risk. Identifying these strategies and ascertaining how well or poorly they work will have implications for the support necessary during posttest counseling and will help personalize the discussion of anticipated risks and benefits of testing. Taking a brief history of past and current psychiatric symptoms (e.g., depression, extreme anxiety, or suicidality) will allow for an assessment of whether this individual is at particular risk of adverse effects after disclosure of results. In such cases, further psychological assessment may be indicated.
In addition, cognitive deficits in the person being counseled may significantly limit understanding of the genetic information provided and hinder the ability to give informed consent and may also require further psychological assessment. Emotional responses to cancer risk may also affect overall mood and functioning in other areas of life such as home, work, and personal health management, including cancer screening practices.[107] Education and genetic counseling sessions provide an ongoing opportunity for informal assessment of affective and cognitive aspects of the communication process. Since behavioral factors influence adherence to screening and surveillance recommendations, consideration of emotional barriers is important in helping a person choose prevention strategies and in discussing the potential utility of genetic testing.[108,109]
The discussion of issues such as history of depression, anxiety, and suicidal thoughts or tendencies requires sensitivity to the individual. The individual must be assured that the counseling process is a collaborative effort to minimize intrusiveness while maximizing benefits. Determining whether the individual is currently receiving treatment for major psychiatric illness is an important part of the counseling process. Consultation with a mental health professional familiar with psychological assessments may be useful to help the provider develop the strategies for these discussions. It also may be beneficial for the individual to be given standard psychological self-report instruments that assess levels of depression, anxiety, and other psychiatric difficulties that he or she may be experiencing. This step provides objective comparisons with already established normative data.[110,111]
In addition to the clinical assessment of psychological functioning, several instruments for cancer patients and people at increased risk of cancer have been utilized to assess psychological status. These include the Center for Epidemiological Studies-Depression scale,[112] the Profile of Mood States,[113] the Hospital Anxiety and Depression Scale,[114] and the Brief Symptom Inventory.[115] Research programs have included one or more of these instruments as a way of helping refine the selection of people at increased risk of adverse psychosocial consequences of genetic testing. Psychological assessments are an ongoing part of genetic counseling. Some individuals with symptoms of increased distress, extreme avoidance of affect, or other marked psychiatric symptoms may benefit from a discussion with, or evaluation by, a mental health professional. It may be suggested to some people (generally, a very small percentage of any population) that testing be postponed until greater emotional stability has been established.
In addition to assessing the family history of cancer, the family as a social system may also be assessed as part of the process of cancer genetic counseling. Hereditary susceptibility to cancer may affect social interactions and attitudes toward the family.[116]
In assessing families, characteristics that may be relevant are the organization of the family (including recognition of individuals who propose to speak for or motivate other family members), patterns of communication within the family, cohesion or closeness of family members (or lack thereof), and the family beliefs and values that affect health behaviors. Ethnocultural factors may also play an important role in guiding behavior in some families.
Assessment also evaluates the impact of the family’s prior experience with illness on their attitudes and behaviors related to genetic counseling and testing. Prior experience with cancer diagnosis and treatment, loss due to cancer, and the family members’ interaction with the medical community may heavily influence attitudes toward receiving genetic information and may play a major role in the emotional state of individuals presenting for genetic services.
The practitioner may use the above framework to guide inquiries about the relationship of the individual to (1) the affected members of the family or (2) others who are considering or deciding against the consideration of genetic counseling or testing. Inquiries about how the family shares (or does not share) information about health, illness, and genetic susceptibility may establish whether the individual feels under pressure from other family members or anticipates difficulty in sharing genetic information obtained from counseling or testing. Inquiries about the present health (new diagnoses or deaths from cancer) or relationship status (divorce, marriage, grieving) of family members may inform the provider about the timing of the individual’s participation in counseling or testing and may also reveal possible contraindications for testing at present.
Evidence from a study of 297 persons from 38 Lynch syndrome–affected families suggested that the timing of genetic counseling and testing services may influence psychological test-related distress responses. Specifically, family members in the same generation as the proband were more likely to experience greater test-related distress with increasingly longer lengths of time between the proband’s receipt of MMR pathogenic variant results and the provision of genetic counseling and testing services to family members. However, it was unclear whether time lapses were due to a delay in the proband communicating test results or the family member choosing to delay genetic testing, despite being aware of the proband’s results.[117]
More specific information about family functioning in coping with hereditary cancers can be found in the psychosocial or counseling sections of PDQ summaries on the genetics of specific types of cancer. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer for more information.)
Specific clinical programs for risk management may be offered to persons with an increased genetic risk of cancer. These programs may differ from those offered to persons of average risk in several ways: screening may be initiated at an earlier age or involve shorter screening intervals; screening strategies not in routine use, such as screening for ovarian cancer, may be offered; and interventions to reduce cancer risk, such as risk-reducing surgery, may be offered. Current recommendations are summarized in the PDQ summaries addressing the genetics of specific cancers.
The goal of genetic education and counseling is to help individuals understand their personal risk status, recognize their options for cancer risk management, and explore their feelings regarding their personal risk status. Counseling focuses on obtaining and giving information, promoting autonomous decision making, and facilitating informed consent if genetic testing is pursued.
Optimally, education and counseling about cancer risk includes providing the following information:
When a clinically valid genetic test is available, education and counseling for genetic testing typically includes the following:
If a second session is held to disclose and interpret genetic test results, education and counseling focuses on the following:
The process of counseling may require more than one visit to address medical, genetic testing, and psychosocial support issues. Additional case-related preparation time is spent before and after the consultation sessions to obtain and review medical records, complete case documentation, seek information about differential diagnoses, identify appropriate laboratories for genetic tests, find patient support groups, research resources, and communicate with or refer to other specialists.[1]
Information about inherited risk of cancer is growing rapidly. Many of the issues discussed in a counseling session may need to be revisited as new information emerges. At the end of the counseling process, individuals are typically reminded of the possibility that future research may provide new options and/or new information on risk. Individuals may be advised to check in with the health care provider periodically to determine whether new information is sufficient to merit an additional counseling session. The obligation of health care providers to recontact individuals when new genetic testing or treatment options are available is controversial, and standards have not been established.[2,3]
Using probability to communicate risk may overestimate risk certainty; this is especially true when risk estimates have wide confidence intervals or when the patient has characteristics that differ greatly from that of the sample that the risk estimate was based on. Finally, there are wide variations in individuals’ level of understanding of mathematical concepts (i.e., numeracy). For all the above reasons, conveying risk in multiple ways, both numerically and verbally, with discussion of important caveats, may be a useful strategy to increase risk comprehension. The numerical format that facilitates the best understanding is natural frequencies because frequencies include information concerning the denominator, the reference group to which the individual may refer. In general, logarithmic scales are to be avoided.[4] Additionally, important “contextual” risks may be included with the frequency in order to increase risk comprehension; these may include how the person’s risk compares with those who do not have the risk factor in question and the risks associated with common hazards, such as being in a car accident. Additional suggestions include being consistent in risk formats (do not mix odds and percentages), using the same denominator across risk estimates, avoiding decimal points, including base rate information, and providing more explanation if the risk is less than 1%.
The communication of risk may be numerical or visual. Use of multiple strategies may increase comprehension and retention of cancer genetic risk information.[4] Recently, use of visual risk communication strategies has increased (e.g., histograms, pie charts, and Venn diagrams). Visual depictions of risk may be very useful when working with visual learners, but research that confirms this is lacking.[5,6] A study published in 2008 examined the use of two different visual aids to communicate breast cancer risk. Women at an increased risk of breast cancer were randomized to receive feedback via a bar graph alone or a bar graph plus a frequency diagram (i.e., highlighted human figures). Overall results indicated that there were no differences in improved accuracy of risk perception between the two groups. However, there was a greater improvement in accuracy of risk perception among the group of women who inaccurately perceived very high risk at baseline and received both visual aids.[7]
Studies have examined novel channels to communicate genetic cancer risk information, deliver psychosocial support, and standardize the genetic counseling process for individuals at increased risk of cancer.[8–15] Much of this literature has attempted to make the genetic counseling session more efficient or to limit the need for the counselor to address basic genetic principles in the session to free up time for the client’s personal and emotional concerns about his or her risk. For example, the receipt of genetic feedback for BRCA1/BRCA2 and mismatch repair gene testing by letter, rather than a face-to-face genetic counseling feedback session, has been investigated.[16] Other modalities include the development of patient assessments or checklists, CD-ROM programs, and interactive computer programs.
A prospective study evaluated the effects of a CD-ROM decisional support aid for microsatellite instability (MSI) tumor testing in 239 colorectal cancer patients who met the revised Bethesda criteria but who did not meet the Amsterdam criteria.[17] The study also tested a theoretical model of factors influencing decisional conflict surrounding decisions to pursue MSI tumor testing. Within the study, half of the sample was randomly assigned to receive a brief description of MSI testing within the clinical encounter, and the other half was provided the CD-ROM decisional support aid in addition to the brief description. The CD-ROM and brief description intervention increased knowledge about MSI testing more than the brief description alone did. As a result, participants felt more prepared to make a decision about the test and had increased perceived benefits of MSI testing.
Other innovative strategies include educational materials and interactive computer technology. In one study, a 13-page color communication aid using a diverse format for conveying risk, including graphic representations and verbal descriptions, was developed.[11] The authors evaluated the influence of the communication aid in 27 women who were at high risk of having a BRCA1/BRCA2 pathogenic variant. They compared these women with a sample of 107 women who received standard genetic counseling. Improvements in genetic knowledge and accuracy of risk perception were documented in those who had read the aid. There were no differences in anxiety or depression between groups. Personalized, interactive electronic materials have also been developed to aid in genetic education and counseling.[12,13] In one study, an interactive computer education program available prior to the genetic counseling session was compared with genetic counseling alone in women undergoing counseling for BRCA1/BRCA2 testing.[13] Use of the computer program prior to genetic counseling reduced face-time with the genetic counselor, particularly for those at lower risk of a BRCA1/BRCA2 pathogenic variant. Many of the counselors reported that their client’s use of the computer program allowed them to be more efficient and to reallocate time spent in the sessions to clients’ unique concerns.
Videoconferencing is an innovative strategy to facilitate genetic counseling sessions with clients who cannot travel to specialized clinic settings. In 37 individuals in the United Kingdom, real-time video conferencing was compared with face-to-face counseling sessions; both methods were found to improve knowledge and reduce anxiety levels.[14] Similarly, teleconferencing sessions, in which the client and genetic specialists talked with each other in real time, were used in rural Maine communities [15] for pediatric genetic consults. These sessions were used to convey genetic information and developmental delays. These sessions resulted in comparable decision-making confidence and session satisfaction when contrasted with in-person consultations. An Australian study compared the experiences of 106 women who received hereditary breast and ovarian cancer (HBOC) genetic counseling via videoconferencing with the experiences of 89 women who received counseling face to face. Pre- and 1-month postcounseling assessments revealed no significant differences in knowledge gains, satisfaction, cancer-specific anxiety, generalized anxiety, depression, and perceived empathy of the genetic counselor.[18]
Posttest counseling may include consideration of the implications of the test results for other family members. It has been suggested that some individuals affected by an inherited disorder agree to have genetic testing performed in order to acquire information that could be shared with family members. There is evidence that implementation of a follow-up counseling program with the proband, after test results are revealed, will significantly increase the proportion of relatives informed of their genetic risk. Follow-up counseling may include telephone conversations with the proband verifying which family members have been contacted and an offer to assist with conveying information to family members.[19] Some experts have suggested that if a test result is positive, plans should be made at this time for the notification, education, and counseling of other relatives based on the test result of the individual. Written materials, brochures, or personal letters may aid people in informing the appropriate relatives about genetic risk.
When a test result is negative, the posttest session may be briefer. It is important, however, to discuss genetic, medical, and psychological implications of a negative result in a family with a known pathogenic variant. For example, it is essential that the person understand that the general population risks for relevant cancer types still apply; additionally, the person’s individual risk of cancer may still be influenced by other risk factors and family history from the other side of the person’s family. Furthermore, people may feel distress even when a test is negative. This outcome has been documented in the context of BRCA1/BRCA2 pathogenic variant testing [20] and may also be anticipated in other cancer susceptibility testing. Posttest results discussion of such distress may lead to referral for additional counseling in some cases.
Many individuals benefit from follow-up counseling and consultation with medical specialists after disclosure of test results. This provides an opportunity for further discussion of feelings about their risk status, options for risk management including screening and detection procedures, and implications of the test results for other family members.
Cascade genetic testing refers to the process of offering genetic testing to biologic family members who are at risk of inheriting the pathogenic variant previously identified in their relative. The process is repeated as additional pathogenic variant carriers are identified within a family. Cascade testing provides the opportunity to identify carriers of a pathogenic variant prior to cancer presentation, which allows opportunities for cancer prevention, early detection, risk reduction, and ultimately, improved health outcomes.[21] There is wide variation in how cascade testing is conducted internationally; this section currently focuses on cascade testing in the United States.
The dissemination of genetic risk information, from the proband to at-risk relatives, is essential for the uptake of cascade testing. Traditionally, this has consisted of discussions regarding the importance of result dissemination to at-risk relatives identified through the proband’s pedigree; this may be supplemented with a letter or educational materials that the proband can use to facilitate disclosure to family members.[22,23]
Most studies evaluating the uptake of cascade testing have been done in either HBOC or Lynch syndrome. A systematic evidence review including both HBOC and Lynch syndrome studies found that notification of the family pathogenic variant by the proband in HBOC families ranged from 21% to 44%. First-degree relatives (FDRs), females, and close family members were more likely to be informed. Testing rates varied depending on the study, with 15% to 57% undergoing genetic testing.[24] In Lynch syndrome, studies reported higher rates of the proband providing variant notification ranging from 41% to 94%, with one study reporting 70% of FDRs undergoing testing.[24] However, another study of carriers of pathogenic variants in a gynecologic oncology clinic found high rates of disclosure (87% of FDRs) yet a relatively low uptake of testing, particularly for Lynch syndrome compared with HBOC (33% vs. 49%, respectively; P = .02).[25]
Emotional barriers found to influence communication of pathogenic variant results to family members include loss of contact and lack of a close emotional relationship,[26] transmission of guilt,[27] anxiety about cancer risks in relatives,[27] concerns that family members would have difficulty understanding the results,[28] emotional difficulties for the relative receiving the information,[26] and negative impacts on family relationships and dynamics.[29–34] Similarly, one study found that patients who reported comfort with discussing health information (P = .012) and/or high communication strength within the family (P = .05) were more likely to disclose positive genetic test results for HBOC and Lynch syndrome.[25] In a qualitative study that focused on family communication, ethnically diverse carriers of BRCA1/BRCA2 pathogenic variants received genetic counseling and testing through a county hospital or a tertiary cancer center. This had no influence on overall rates of disclosure of results to family members (73%). However, individuals of African American and Asian/Pacific Islander heritage were less likely to disclose results (47% and 70%, respectively), when compared with individuals of White heritage (91%). Additionally, African Americans were less likely to undergo testing (odds ratio, 0.16; 95% confidence interval, 0.06–0.40).[35]
In a retrospective study of FDRs of a proband with a pathogenic or likely pathogenic variant, 14% of FDRs who were given the information found the information very or somewhat hard to understand. FDR recall of the test result was concordant with the actual test result in 82% of cases; however, 10% were unable to recall the result.[36]
Several strategies aimed at facilitating family dissemination and testing uptake have been studied.
The Finland Lynch syndrome Registry studied reaching out to at-risk family members through letters. Family members (N = 446) at 50% risk of developing Lynch syndrome from 36 families were notified through letters, which offered genetic counseling and testing for the documented variant in the family. Of the 446 family members, 347 underwent genetic counseling, with 75% of the entire cohort (n = 334) opting for testing.[37]
Establishment of the Family Information Service at Creighton University provided group counseling sessions to at-risk relatives attending an education session. Group sizes ranged from 15 to 75 individuals and sessions were conducted by genetic nurses and counselors in a location near family residences. While an uptake rate of testing was not reported, these sessions considerably reduced the one-on-one health care provider time, thus increasing the capacity of the genetic clinic.[38]
Some groups have studied strategies to prepare probands to disseminate genetic test results to at-risk relatives. A randomized controlled study explored training on a six-step communication strategy that consisted of identifying at-risk relatives, selecting the communication method, assessing family member knowledge, sharing the result, responding to reactions, and providing genetic counseling resources. No significant difference in the rate of genetic test result dissemination between intervention (n = 137) and control groups (n = 112) was detected.[39]
A Netherlands group explored the feasibility of a two-phased telephone motivational interviewing intervention conducted by five trained psychosocial workers. Consultands (n = 144) included those with at least one relative eligible for genetic testing or cancer screening. Phase 1 determined the agenda, confirmed which family members needed to be informed with the proband, and explored current and planned result-sharing mechanisms. Phase 2 focused on sharing certain information, building motivation and self-efficacy, and brainstorming solutions to dissemination barriers. Outcomes showed that consultands found this strategy feasible and acceptable. A randomized study is under way to evaluate whether this intervention increases information dissemination.[40]
An Australian randomized controlled trial evaluated the impact of additional telephone genetic counseling support in individuals who had been diagnosed with a genetic condition, had a child diagnosed with a genetic condition, or were found to be carriers of a pathogenic variant. Additional telephone counseling in the intervention group (n = 45) occurred 2 to 3 times over 12 months, which was compared with controls (n = 50). No significant difference in relatives seeking genetic services was detected.[41]
One study explored free genetic testing for at-risk relatives. In a BRCA1/BRCA2 pathogenic variant cohort (n = 115) eligible for free at-risk family member testing, 77% disclosed results to all at-risk family members. Only 60% of FDRs and 47% of more-distant relatives underwent genetic testing.[42]
Genetic testing laboratories are also exploring ways to reduce barriers to testing for family members, given that the uptake of cascade testing is low.[24,25] Some laboratories now offer low-cost self-pay testing or no-cost genetic testing to FDRs within a specified time period (e.g., 90 or more days) of a pathogenic or likely pathogenic variant being identified in a family member.[43,44] Outcomes from these efforts have not yet been reported.
One study performed cancer predisposition genetic testing on the basis of a diagnosis of a solid tumor cancer in patients unselected for family history or guideline-specified testing. In individuals found to harbor a pathogenic variant, all biological family members of the probands were offered no-cost testing for a 3-month period. Of the eligible families, 17.6% had one or more family members undergo genetic testing. A median of two individuals per family were tested (range, 1–14), although the total number of family members eligible for testing was not reported.[45]
One direct-to-consumer cancer genetic testing laboratory that performs only a 30-gene panel offered reduced-cost ($50) testing to FDRs of individuals found to harbor a pathogenic variant. Individuals were emailed information about the family testing program, and those interested who applied (n = 1,101) identified the at-risk FDRs and provided their contact information. The laboratory sent emails to FDRs inviting them to undergo testing for the 30-gene panel, which included the pathogenic variants found in their relatives. In 1 year of follow-up, 48% of the invited FDRs underwent testing. Only 12% of FDRs who were tested and found to have a pathogenic variant continued cascade testing of their own FDRs. Notably, 5% of FDRs were found to have pathogenic variants in genes other than the ones found in their family members. Additionally, 16.8% of FDRs were found to have a variant of uncertain significance.[46]
A systematic evidence review studied the dissemination of genetic test results to the probands’ family members, using contact information that was provided by probands. Results showed that the number of probands tested was higher than the number of relatives who had been notified of the probands’ results. Four studies also found that relatives did not understand the genetic test results; however, when sufficiently informed by a health care provider, most opted to be tested.[24]
Similarly, in a study with 30 probands who had a pathogenic variant, 114 at-risk relatives were identified. Ultimately, probands gave permission for the study coordinators to contact 102 of the at-risk relatives. Of those relatives, 95 of 102 (93%) were successfully contacted by a member of the genetics team, 92 (97%) agreed to genetic counseling, 82 (86%) agreed to testing, and 66 (70%) completed testing for the variant in the family.[21]
When done in a clinical setting, there may be other considerations, such as billing and institutional privacy regulations, that need to be investigated before pursuing direct contact with family members.
Chatbots use artificial intelligence to create an online avatar that can speak back and forth with users, simulating real conversations on the basis of pre-established text-based dialogues.[47] Chatbots are actively being explored as a mechanism to respond to family member cascade testing queries.
In summary, these studies document that relying on probands to notify family members of genetic risk has limitations affecting both information dissemination and the uptake of testing. No one strategy has been shown to be optimal.[48]
Ethical, legal, and social issues related to cascade testing, such as duty to warn and disclosure to at-risk relatives, are discussed in the Ethical, Legal, and Social Implications section of this summary.
Cancer risk assessment counseling is a multistep process that traditionally included an in-person pretest and posttest counseling session. In an effort to overcome access barriers, other modalities have been implemented, including group sessions, telephone counseling, and online genetic counseling using remote videoconferencing, which is often referred to as telegenetics.[1–10] Of these other modalities, only telephone counseling has been examined for noninferiority against in-person genetic counseling in a randomized controlled trial.[11–14]
A systematic review identified 13 published studies that used a randomized controlled trial design to compare pretest and posttest outcomes for in-person genetic counseling with telephone counseling. Knowledge and psychosocial outcomes (e.g., distress) were found to be noninferior, equivalent, or not statistically significant between telephone counseling and in-person counseling. Two studies demonstrated lower testing intention or uptake among participants who received telephone counseling. The majority of studies also found no difference in satisfaction; however, two studies demonstrated higher satisfaction among individuals who received telephone compared with those who received in-person genetic counseling.[14] A subsequent study examined several dimensions of patient perceptions of genetic counseling among participants of a randomized trial of telephone versus in-person genetic counseling.[15] In the 2-week period after their pretest genetic counseling appointment, participants who had telephone-based counseling were more likely to rate it as convenient; however, they also reported lower levels of support and emotional recognition by the counselor. There were no differences in overall satisfaction. Exploratory analysis demonstrated minority participants reported lower perceptions of counselor support with in-person counseling compared with telephone counseling, while the opposite was observed for non-Hispanic White participants. Additional studies are needed to confirm these findings given the small sample size. (The studies were conducted prior to the adoption of multigene panel testing.)
Another group reported results of a study in which all participants (N = 1,178) received in-person pretest counseling at one of five participating sites. Those participants willing to be randomized had their results disclosed by telephone (n = 401) or in person (n = 418). Notably, 30% of participants in this study had multigene panel testing. In this trial, telephone disclosure was noninferior to in-person results disclosure when comparing primary psychosocial outcomes (e.g., general and state anxiety). In primary analysis, knowledge did not meet the threshold of noninferiority without imputing missing data. Secondary outcomes related to cancer distress, depression, uncertainty, satisfaction with genetic testing, and behavioral intentions for risk management strategies were not statistically significant between groups.[16]
Studies have also examined the use of online genetic counseling using remote videoconferencing (telegenetics) as an alternative to in-person genetic counseling and demonstrated increases in patient knowledge, high levels of satisfaction, and minimal negative psychosocial outcomes.[17–20]
Emerging approaches to delivering clinical genetic services have been examined to facilitate greater access to genetic counseling and testing. These approaches have been utilized to streamline the process by which high-risk or affected individuals are identified and referred to genetic services. These service delivery models vary in the processes by which patients receive genetic education, counseling, and testing, with genetic counseling increasingly taking place only after genetic testing has already occurred.
Several factors have contributed to the provision of genetic testing without pretest genetic counseling. These factors include: (1) expansion of genetic testing criteria, resulting in increased demand for genetic testing; (2) more indications for testing at the time of cancer diagnosis, given that the identification of a pathogenic variant may affect treatment options (e.g., poly [ADP-ribose] polymerase [PARP] inhibitors in BRCA1/BRCA2 positive patients with metastatic human epidermal growth factor receptor 2–negative breast cancer, ovarian cancer, or pancreatic cancer); (3) increasing numbers of patients who undergo tumor genomic testing to guide treatment, which may be followed by confirmatory germline testing; (4) increasing availability of universal testing (e.g., for ovarian, pancreatic, and prostate cancer patients) and consumer-directed genetic testing. Some indications have resulted in patients being offered genetic testing by their health care providers in a nongenetics environment (e.g., by primary care providers, surgeons, or oncologists), which may then be followed by posttest result interpretation and counseling by the provider or via a genetics specialist.
Studies have examined the impact of embedding a cancer genetic counselor on site in gynecologic oncology clinics in efforts to increase referral to and the use of genetic counseling among affected women.[21–23] Improvements were observed in referral rates (up to 85%) and genetic counseling uptake following the incorporation of an on-site genetic counselor. Studies reported reductions in time spent with patients by the genetic counselor,[21] as well as the duration of time between referral to scheduling and completion of a genetic consultation.[22,23]
Universal germline genetic testing is now standard practice for patients with certain cancers, including ovarian, pancreatic, and metastatic prostate cancers.[24] (Refer to the Clinical Application of Genetic Testing for Inherited Prostate Cancer section in the PDQ summary on Genetics of Prostate Cancer for more information about genetic testing in prostate cancer patients.)
The most long-standing guidelines available for universal testing is in ovarian cancer. National guidelines in the United States [24–26] and internationally [27,28] recommend offering genetic testing to all women with ovarian cancer. There are two primary reasons for the endorsement of universal testing in this patient population, given that up to 15% of ovarian cancer patients harbor a pathogenic variant in BRCA1 or BRCA2:[29,30] (1) to identify patients who may benefit from targeted therapy with a PARP inhibitor, such as olaparib; and (2) to facilitate the identification of at-risk relatives through the process of cascade testing.[24,25,31]
In response, some practices have implemented strategies focused on universal referral and genetic testing for ovarian cancer patients.[23,32,33] In one study, the deployment of universal referral of 100 newly diagnosed ovarian cancer patients by gynecologic oncologists, along with outreach by a genetics navigator to schedule genetic counseling appointments, resulted in a counseling uptake rate of 78% and a testing uptake rate of 73% over a 3-year period. Notably, patients treated at a public hospital were significantly less likely to undergo genetic counseling compared with patients at a private hospital (56% vs. 84%, P < .05). There was also a trend towards lower uptake among Hispanic patients compared with non-Hispanic White patients (63% vs. 75%, P = .09).[33]
At another academic gynecologic oncology site, several processes were implemented including provider and patient education on the rationale behind universal genetic testing, electronic health records modifications to facilitate communication with patients and recommend genetics referral, point-of-care scheduling for genetic counseling at check out, and updates to tumor board conference documentation to include whether genetic counseling was recommended. Uptake of genetic testing increased from 27% to 82% after implementation of these processes over a 3-year period.[32]
Another institution implementing universal genetic testing across gynecologic oncology clinics also reported genetic testing rates that exceeded 80% over a 3-year period.[23] Notably, different service delivery models were used across clinics to optimize the ability to overcome site constraints and barriers affecting patient access to genetic counseling and testing. These models included (1) physician-coordinated genetic counseling at locations without a genetic counselor on site (triaged/streamlined model), and (2) integrated genetic counseling within the clinic (embedded model).
High-risk populations, such as those of Ashkenazi Jewish decent, may be offered genetic testing with no pretest counseling or a streamlined education process that includes the provision of written or other materials.[34–37] Uptake of BRCA1/BRCA2 testing was 67%, and satisfaction with the population screening approach was greater than 90% at both 1 week and 6 months posttesting.[34] Posttest genetic counseling was offered in person for carriers and noncarriers of BRCA1/BRCA2 pathogenic variants with a significant family history of cancer; letters detailing test results and general screening recommendations were sent for noncarriers with limited family history. Compliance with posttest counseling was 100% for carriers and 87% for noncarriers with a suggestive family history. Notably, gender differences in compliance were found among noncarriers (89% for women vs. 78% for men; P = .01).[34]
Nongenetics providers who receive training in cancer genetics are increasingly being used in triaged models to increase access to cancer genetics services. These providers may be engaged at different time points along the risk assessment, counseling, and testing process. In one example, nurses were trained to provide basic risk assessment and offer BRCA testing to patients in an effort to increase access to genetic service providers in rural settings.[38] Family histories collected via a paper screener administered in mammography or oncology sites were reviewed and triaged by the genetic counselor on the basis of risk status, and subsequent counseling regarding risk was provided by either the nurse or the genetic counselor. A fourfold increase in the number of patients seen at the site was observed over a 2-year period.
In the context of gynecologic oncology, some methodologies have streamlined processes such that oncology physicians conduct pretest education and counseling, informed consent, genetic testing, and return of negative results, while triaging the return of positive or variants of unknown significance results to genetic counselors.[23,39] Patient satisfaction with oncologist-led counseling and testing was reported as high, with more than 99% of patients expressing satisfaction in one study.[39]
Streamlined services have also been deployed at obstetric and gynecologic practices without subsequent triaging and referral to genetic counselors. In a study of five community obstetrics and gynecologic practices, clinicians were trained in hereditary cancer risk assessment and clinics modified patient screening and workflows. After 8 weeks of deploying the modified workflow, 92.8% (3,811/4,107) of patients were assessed for hereditary cancer risk and 23.8% (906/3,811) of those assessed met National Comprehensive Cancer Network (NCCN) guidelines for genetic testing. Among those who met guidelines, 89.7% (813/906) were offered genetic testing by the clinicians. Overall, 26.7% (219/813) of the women provided samples for testing and 20% (165/813) received their results. Satisfaction with the process was high (~97%).[40]
However, another study involving nongenetics providers in the delivery of genetics services revealed suboptimal outcomes. A study of a single national health insurer in the United States revealed that 37% of women who obtained BRCA1/BRCA2 genetic testing received genetic counseling from a genetics provider prior to testing.[41] Patients who did not receive pretest genetic counseling by genetics providers were less likely to meet criteria for testing and had lower levels of knowledge, understanding, and satisfaction related to the genetic testing process.
The identification of hereditary cancer risks in patients, through a pedigree-based approach, clinical diagnosis, and/or the results of genetic testing, has implications for both patients and their biological family members. One of the major components of genetic counseling, as recommended by many professional medical societies, is to inform patients about familial risk and to encourage discussion with relatives.[1–6] (Refer to the Strategies to facilitate cascade genetic testing section of this summary and the Family communication about genetic testing and hereditary risk section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about disclosure to at-risk relatives.)
When patients do not inform their at-risk relatives about potentially actionable genetic risks (e.g., pathogenic variants in high-risk genes such as BRCA1 or BRCA2) or do not give their providers permission to share these results, providers may face a dilemma about their duty to warn the relatives. There are several ethical and legal considerations that factor into decisions about what responsibility, if any, providers have to directly inform at-risk relatives about hereditary cancer risks.
If a provider is considering overriding patient confidentiality or consent to directly notify relatives about genetic information, it is important to consider a consultation with one or more of the following: ethicist, ethics committee, legal counsel, privacy officer, and, if applicable, institutional review board to assure adherence to local ethical standards and legal, regulatory, and privacy requirements.
Patients are encouraged to provide information to at-risk relatives about family history and genetic testing results that reveal pathogenic or likely pathogenic variants, especially for variants with moderate-to-high cancer risks and for which screening and risk reduction options may be guided by those results.
If a patient declines to notify at-risk relatives, there may be circumstances wherein it could be permissible for the provider to consider directly contacting and notifying the relatives. Such circumstances may include the following:[5]
In practice, a provider pursuing a justified breach of confidentiality in order to inform at-risk relatives is uncommon.
It is possible that the patient refuses to inform family members but gives permission for their provider to directly contact their at-risk relatives. In such instances, it is important to document the patient’s consent and consider the optimum methods for communicating with relatives, as well as the provider’s resources to follow-up with such requests.[7] In addition, even when the patient consents to the provider contacting relatives directly, it is important to consider a consultation with one or more of the following: ethicist, ethics committee, legal counsel, privacy officer, and, if applicable, institutional review board to assure adherence to local ethical standards and legal, regulatory, and privacy requirements.
Many providers may not have access to information about the identity of at-risk relatives or have no way to confirm that contact information for at-risk relatives is correct. Thus, in practice, the dilemma about a provider’s duty to warn relatives arises when the provider treats more than one individual in a family or has had prior or ongoing contact with family members.
(Refer to the Strategies to facilitate cascade genetic testing section of this summary and the Family communication about genetic testing and hereditary risk section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about informing at-risk relatives.)
There are very few legal precedents that guide whether the duty to directly warn family members is the responsibility of the patient or the provider. The two most prominent cases related to hereditary cancer risk, Pate v Threlkel (medullary thyroid cancer) and Safer v Pack (familial adenomatous polyposis), are also dated (1995 and 1996, respectively) and may have the most relevance only in the states in which the cases were adjudicated (Florida and New Jersey, respectively).[8,9] These cases and the potential implications of their holdings are discussed elsewhere.[10–14]
In deciding whether there may be a duty to warn at-risk relatives about hereditary risk, it is important to balance the bioethical constructs of beneficence and nonmaleficence (providing benefit and avoiding harm, respectively) and autonomy with other factors such as professional societies’ recommendations, state and federal legislation, and court holdings from various states. The definition of genetic information (related to hereditary risk) may vary depending on the legal case and the language used in state and federal legislation, although it generally encompasses genetic testing, as well as family history information. The information below pertains to guidance in the United States, as there is variability in international perspectives and policies.[15–18]
Many professional medical societies and government agencies have published their positions and recommendations on communication between a health care provider and a patient’s relatives in regard to disclosure of genetic risk. Several organizations such as the American Medical Association, American Society of Clinical Oncology, National Society of Genetic Counselors, and the International Society of Nurses in Genetics recommend that patients who undergo genetic testing disclose the information directly to their at-risk relatives and do not recommend provider notification of relatives without consent. However, the American Society of Human Genetics, which encourages individuals to notify their relatives directly, also provides an explication for criteria where it may be ethically permissible for providers to directly notify at-risk relatives.[5]
At the federal level, there are strict nondisclosure policies governing private health information.[10] The Standards for Privacy of Individually Identifiable Health Information (Privacy Rule), which summarizes the Health Insurance Portability and Accountability Act (HIPAA) of 1996, finds it permissible to disclose health information without consent when the public interest is at risk;[19,20] therefore, under certain conditions, exceptions to the nondisclosure policy include the following:
In addition, HIPAA contains a minimum necessary standard, which means that entities that are subject to such regulation can request, and receive, only information relevant to a specific purpose.[21] The type and extent of genetic information that can be released to relatives depends on whether the data were obtained through research and whether the implications relate to public health or in the context addressed herein, to support clinical medical decision making.[21] For example, in some instances it may be permissible for the physician of a genetically tested patient to share those results with a relative’s physician if they are relevant to management recommendations.[21] The interpretation of this standard relates to disclosure to another provider, not the at-risk relatives directly.
At the state level, there is significant variability in statutes as they relate to genetic privacy and when, how, by, and to whom genetic information can be released. The National Human Genome Research Institute at the National Institutes of Health maintains the Genome Statute and Legislative Database, which is updated regularly.
If there is a question about whether it is appropriate to breach patient confidentiality to warn relatives, it is important to review these regulations, as well as federal and case law with an ethicist, ethics committee, legal counsel, and/or privacy officer to ensure adherence to local ethical standards and legal, regulatory, and privacy requirements.
The section above primarily addresses the duty to warn relatives when a living patient is unwilling to do so. However, concerns also exist about disclosure of genetic testing results from deceased individuals. This concern has arisen in research contexts related to targeted research findings (i.e., findings directly related to the study at hand) or secondary findings, in biobanks, and in clinical contexts.[22–25] Pragmatic tools for returning research results are available elsewhere.[26]
In clinical practice, the duty to warn about genetic testing results in a deceased individual has arisen after such testing is performed as part of an autopsy (e.g., revealing an inherited cause for sudden cardiac death).[27,28] However, in the clinical oncology setting, the question about providers disclosing a decedent’s test result to at-risk relatives may occur in several contexts. Examples include the following:
In anticipation of these possible scenarios, many genetics providers ask patients to sign a form designating which individuals they would like to have access to their genetic testing results.[26,29] This form can specify whether this disclosure can occur after death, regardless of whether the patient had received the results. The form contains the relatives’ full names, relationships to the patient, postal addresses, and if possible, mobile phone numbers and email addresses.
HIPAA is a federal law that applies to protected health information in living and deceased individuals.[30] Unless the deceased individual had expressly stated that genetic testing results should not be shared, under HIPAA, after all relevant points of the law have been considered, it may be possible that this information could be shared with relatives.[30,31]
Before contacting relatives about genetic testing results for a deceased individual, it is important to check with a privacy officer or legal counsel to determine if there are specific regulations that apply or whether documentation is required (e.g., demonstrating who the personal representative is/was for the decedent). In addition, an ethicist, ethics committee, and if applicable, institutional review board may also be consulted to ensure adherence to local ethical standards and legal, regulatory, and privacy requirements.
Traditionally, the duty to warn refers to a potential responsibility to notify a patient’s at-risk biological relatives, such as children and siblings, about a serious hereditary risk. However, more recently, questions have arisen about the duty to warn or duty to rescue the person being tested on the basis of the identification of secondary genomic findings, or genomic testing results that are potentially actionable but were not sought out as part of the indication for testing.[32]
For example, the American College of Medical Genetics and Genomics (ACMG) recommends that pathogenic variants in 59 genes, including 25 genes associated with 17 cancer/neoplastic syndromes should be reported any time an adult or child undergoes clinical genomic sequencing, regardless of the indication.[33,34] The ACMG has clarified their position to note that the list of genes was not intended or validated for use in population screening.[35]
The ACMG also recommends that individuals undergo an informed consent process and that they can opt out of receiving secondary findings.[36,37] Of note, various clinical programs, research programs, and laboratories have devised their own list of genes in which identified pathogenic variants could be released as secondary findings (refer to [38] [eMERGE] and [39] [MyCode/Geisinger]). In many cases, these gene lists are much broader than the one recommended by ACMG. A limitation of the list published by ACMG is that it does not encompass several cancer risk genes that are considered high-to-moderate risk and for which screening and risk-reduction measures may be recommended.[40,41]
However, for many of the genes on the ACMG list, the ACMG and others acknowledge the potential uncertainty about penetrance and, therefore, recommended medical management for individuals who test positive without relevant personal or (known) family history.[35] This consideration may add to the complexity of patient-provider decision making about expanding genetic testing to at-risk relatives.
In light of the complexities associated with possible outcomes of genomic sequencing, approaches to consenting patients about the types of results they would like to receive may include a discussion of the range of potential findings as opposed to a description of the medical implications for pathogenic variants in a host of specific genes.[42,43]
For example, pathogenic variants may be classified as medically actionable, such as those identified in BRCA1/BRCA2 or MSH2. Other variants may be clinically valid but are associated with a range of risk and may have clinical utility limited to specific circumstances. For example, pharmacogenomic variants may not predict disease risk at all but have clinical utility for individuals exposed to certain medications. Another group of variants may reveal carrier status for Mendelian conditions but may have no implications to patients if they do not choose to have children. Carrier testing results may have reproductive implications for their relatives, however. Finally, highly predictive risk variants may be identified that have few options available to lessen disease course or risk (e.g., for amyotrophic lateral sclerosis/Lou Gehrig’s disease or early-onset Alzheimer disease).[43]
Another consideration is that somatic testing of tumors may reveal pathogenic variants that, if confirmed in the germline, may have implications for both the patient tested (e.g., with respect to systemic treatment of the current cancer and risks for other cancers) and his or her relatives.[44–47] This concern may also arise in the context of immunohistochemistry (IHC) or microsatellite instability (MSI) testing of colorectal cancer or uterine tumors, in which testing may be performed primarily to guide treatment of the patient, but subsequent germline testing may also determine whether the patient is affected with Lynch syndrome.[48,49] Considerations about the implications for relatives and the potential benefits of cascade testing in reducing morbidity and mortality from Lynch syndrome are particularly relevant given that universal testing of colorectal and uterine tumors is increasingly performed at the time of diagnosis, which may include tumor sequencing instead of IHC or MSI screening.[50,51] Thus, tests performed on tumor tissue, particularly when followed by confirmatory germline testing, may raise dual concerns about the duty to rescue (the patient) and a possible duty to warn at-risk relatives. (Refer to the Duty to warn considerations section of this summary for more information.) One way to address these concerns is to have patients undergo an informed consent process before any tumor testing to alert them about the importance and implications of germline testing for themselves and their relatives.[52–54]
Genetic information obtained from genetic susceptibility tests may have medical, economic, and psychosocial implications for the individual tested and his or her family members. The potential for employment and insurance discrimination is a common concern for individuals considering genetic testing.[55–58] However, there is limited documentation of employment and insurance discrimination on the basis of hereditary cancer genetic testing results.
(Refer to the Informed Consent subsection of this summary for more information about discrimination issues related to cancer genetics services.)
State and federal legislation statutes have been developed to prevent the use of genetic information for employment practices, such as hiring, promotion, and salary decisions; and insurance policies, including life and health coverage, by employers, schools, government agencies, and insurers.[59] According to Executive Order 13145, federal departments and agencies are prohibited from discriminating against employees on the basis of genetic test results or information about a request for genetic testing services.[60] Employers and insurers are prohibited from intentionally lowering policy rates by using practices such as screening for individuals who are at risk of becoming ill or dying because of genetic disease susceptibility, such as cancer.[60] These provisions were extended by the Genetic Information Nondiscrimination Act (GINA) in 2008. (Refer to the GINA section of this summary for more information.) Federal laws, including GINA, do not cover employer-provided life and disability insurance; however, some states do have legislation addressing the use of genetic information for life and disability policies. Current state statutes and bills may be found through NHGRI’s Genome Statute and Legislation Database, which is a useful resource for patients to consult before undergoing genetic testing. Examples of relevant legislation regarding genetic information are summarized in Table 3. The information in this table is not comprehensive but provides key points only. Refer to the original sources for more information.
| Law | Coverage Examples | Key Limitations | Protects All Americans? |
|---|---|---|---|
| USPSTF = United States Preventive Services Task Force. | |||
| aAdapted from Leib et al.[61], NHGRI [62], and FORCE.[63] | |||
| Civil Rights Act of 1964 | Employment only | Does not apply to health insurance | Yes |
| Applies in instances of discrimination on the basis of genetic information if associated with race or ethnic groups | Strong association with a racial or ethnic group for hereditary cancers is rare | ||
| Americans with Disabilities Act of 1990 | Disabilities associated with manifesting genetic information | Does not apply to health insurance | Yes |
| Health Insurance Portability and Accountability Act of 1996 | Group health insurance plans | Does not stop insurers from requiring genetic tests | Yes |
| Genetic information is not defined | |||
| Forbids excluding an individual in a group health plan due to genetic information | Genetic information can be used for plan underwriting | ||
| Forbids premium increases for different group plan members | Disclosure of genetic information is not restricted | ||
| Preexisting conditions cannot include predictive genetic information | Does not apply to individual health plans, unless covered by the portability provision | ||
| Executive Order 13145 of 2000 | Forbids federal employee workplace genetic discrimination | Does not apply to health insurance | No; excludes members of the United States military and anyone who is NOT a federal employee |
| Only applies to federal employees | |||
| Genetic Information Nondiscrimination Act of 2008 (GINA) (Enacted in 2009) | Forbids genetic discrimination in the workplace and in health insurance | Civil suit is restricted to only those who have had all administrative remedies exhausted | No; excludes members of the United States military, veterans obtaining health care through the Veteran’s Administration, and the Indian Health Service |
| Genetic information broadly defined | |||
| Specific to group and individual insurance plans | |||
| Forbids use of genetic information in underwriting | |||
| Forbids requiring genetic testing by employers and insurers | Does not cover life, disability, and long-term care insurance | ||
| Patient Protection and Affordable Care Act (ACA) (Enacted in 2010) | Group or individual health insurance issuers must provide coverage for all individuals who request it | Health plans can set coverage limits on services that are not considered essential | Yes |
| Eliminates preexisting coverage as a reason to exclude coverage | Screening and preventive medicine coverage have some restrictions | ||
| Eliminates annual and lifetime caps on insurance coverage | Genetic counseling and testing coverage does not apply to everyone (e.g., it does not cover men, Lynch syndrome testing, or women who do not meet USPSTF guidelines for BRCA1/BRCA2 testingExit Disclaimer) | Yes | |
| Caps out-of-pocket costs for health care | |||
| Covers, without a copayment, some cancer screening and preventive services | |||
| Covers genetic counseling and BRCA1/BRCA2 testing for women who meet certain criteria | |||
This U.S. federal law contains many protections against discrimination based on genetic information.[64–67] Examples of specific provisions are as follows:
GINA amends and/or extends coverage of HIPAA, ADA, and the Employee Retirement Income Security Act by including genetic information under medical privacy and confidentiality legislation, and employment and insurance determinations.[68] Additionally, with the passage of GINA, researchers and clinicians can encourage participation in clinical trials and appropriate genetic testing knowing that there are federal protections against discrimination on the basis of the results of genetic testing. GINA established the minimum protection level that must be met in all states. However, for states with more robust legislation in place, GINA does not weaken existing protections provided by state law.
However, GINA has several limitations, including the following:
Under GINA, it is permissible for employers to request employees’ genetic information for the purposes of voluntary wellness programs. However, employers cannot encourage employees to provide their genetic information; this means that if an employee chooses to give genetic information to the wellness program, they cannot receive an additional reward for doing so. Conversely, if an employee chooses to withhold genetic information, they cannot be penalized.[62] Regulations regarding workplace wellness programs have been amended by the U.S. Equal Employment Opportunity Commission, and they are in the process of further revision.[69] Thus, before providing genetic information to such wellness programs, patients should be informed about current regulations and provisions for privacy and confidentiality.
GINA and other state and federal protections do not extend to genetic testing of active duty military personnel or genetic information obtained from active duty military personnel.[70] In the military, genetic testing provides medical information that is to be used to protect military personnel from potentially harmful duties or exposures that could stimulate or aggravate a health problem. For example, use of certain antimalaria medications in individuals with glucose 6-phosphate dehydrogenase deficiency can result in red blood cell rupture. Therefore, some genetic information may be critical for maintaining the health and safety of military personnel, given the possible stressful occupational environments they may face. In addition, all military personnel provide a DNA sample to be maintained in a repository that can be used for identification purposes.[71]
Results of genetic tests for disease predisposition could influence military eligibility for new enlistments. For current military personnel, genetic test results could influence worldwide eligibility, assignments, and promotions.
Thus, it is important for individuals who are considering enlisting in the military or those who are active duty to determine what specific policies apply to them, and what the implications of genetic testing may be for their current and future military career.[56] In addition, they should be aware of the potential implications of clinical and research genetic testing and possible concerns related to direct-to-consumer genomic testing.[72]
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® – NCI’s Comprehensive Cancer Database pages.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about cancer genetics risk assessment and counseling. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Cancer Genetics Risk Assessment and Counseling are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Cancer Genetics Editorial Board. PDQ Cancer Genetics Risk Assessment and Counseling. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/causes-prevention/genetics/risk-assessment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389258]
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