Cancer Genetics Risk Assessment and Counseling (PDQ®): Genetics - Health Professional Information [NCI]
Genetic Testing
Factors to Consider When Offering Testing
Indications for testing
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:[
- An individual has a personal or family history suggestive of a genetic cancer susceptibility syndrome.
- The results of the test can be interpreted.
- Testing will influence medical management.
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.[
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.[
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.[
Genetic education and counseling approaches (including the interpretation of genetic test results) will vary if genetic testing has already been attempted (for more information, see Figure 1). In general, there are two primary circumstances in which genetic testing is performed:
- Families with evidence of an inherited susceptibility that have not had any genetic testing or in which genetic testing has not identified a pathogenic variant.
- Families with a documented pathogenic variant.
Figure 1. This genetic testing algorithm depicts the multistep process of testing for cancer susceptibility.
Value of testing an affected family member first
Genetic susceptibility testing generally yields the most useful information when a living family member with the cancer of concern is tested before other family members; this can help determine if his/her cancer has a genetic origin. If testing is deferred while follow-up with an affected relative is pending, consider providing interim cancer risk management guidelines to the unaffected proband.[
- Pathogenic variant detected.
- No variant detected.
- Variant of uncertain significance (VUS) detected.
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:
- The cancer in the family may be associated with a cancer susceptibility gene other than the gene that was tested.
- The cancer in the family may be associated with a pathogenic variant, but the cancer in the specific family member who underwent testing is not associated with that variant. This can occur especially with cancers that are common in the general population, such as breast cancer or prostate cancer. The family member who is affected with the disease but is not a carrier of the pathogenic variant associated with the inherited predisposition to cancer in the family is considered a phenocopy.
- Identifying a genetic variant may not be possible given the limited sensitivity of the laboratory techniques used to detect genetic variants. There may be additional testing available to detect certain types of variants that would have been missed by the initial genetic test.
- The function of the gene could be altered by a pathogenic variant in a different gene.
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:
- The location of the variant in relation to regions and function of a gene.
- The specific change; since many variants are missense variants, not all amino acid substitutions are as significant.
- Whether the variant has been documented in the presence of a documented pathogenic variant.
- Whether the variant is associated with the branch in the family with the cancer and/or whether the variant tracks with the cancers in the family.
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.
Testing in families with a documented pathogenic variant
Genetic testing for a documented familial pathogenic variant can be informative and will yield one of the following results (for more information, see Figure 1):
- Positive for the familial pathogenic variant.
- Negative for the familial pathogenic variant.
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.[
Insurance coverage
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.[
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.[
Genetic testing and assisted reproductive technology
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.[
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:[
- Does the cancer syndrome include childhood malignancies or significant morbidity or mortality at an early age?
- What is the penetrance associated with the genetic variant?
- How severe is the syndrome phenotype?
- Are there interventions available that decrease the pathogenic variant-associated cancer risk or are proven to detect cancer early when it is in a treatable form?
- Is there evidence of a different phenotype if an individual is a heterozygous or homozygous carrier?[
12 ,13 ]
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.[
Determining the Test to Be Used
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. Several 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.[
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.[
Since hereditary cancer syndromes can have varying presentations and overlapping phenotypes, selecting the appropriate genetic test may require knowledge on the following topics:
- Genetic syndromes.
- Diagnostic methods used for identifying pathogenic variants.
- Correlations between clinical and molecular test findings.
- Information regarding rapidly changing genetic testing options.
See the following summaries for more information:
- 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
- Genetics of Prostate Cancer
Multigene (panel) testing
Next-generation sequencing (NGS) and the removal of most patent barriers to diagnostic DNA sequencing [
Genetic education and counseling for multigene testing
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.[
| Topic | Traditional Germline Cancer Genetic Testing | Multigene Panel Germline Cancer Genetic Testing |
|---|---|---|
| a Adapted from Robson et al.[ |
||
| 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 ofDNAsample(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. | |
Research examining multigene testing
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 regarding multigene testing:
- The studies differ in their aims, approaches, ascertainment of subjects, and panels used.
- Laboratory- and clinic-based studies likely differ regarding their sampling frames (the population a study draws from and its characteristics). For example, some studies may include testing by a wide variety of health care professionals, some of whom may not be as experienced in triaging, testing, and advising high-risk patients.[
22 ] - Testing methodologies also differ among laboratories regarding exon /intron coverage, read depth, Sanger sequencing confirmation, and variant interpretation.[
23 ] - The genes to be tested as part of a multigene panel are constantly changing. In some studies, the composition of multigene panels changed during the course of the study, usually to include more genes.[
24 ] - Some patient populations included a mix of patients already tested by traditional single-gene methods and those undergoing testing for the first time, making it difficult to establish true diagnostic yield.[
25 ,26 ] - In the studies that replicated previous BRCA testing with a panel, the analytic validity of the NGS multigene panel tests is equivalent to the former single-gene tests, with almost 100% concordance in patients who had both single-gene BRCA testing and multigene testing.[
25 ,26 ]
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.[
Selected reports from 2014 to 2018, which included 1,000 to 10,000 tested individuals, showed variation in pathogenic variant and VUS rates.[
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.[
Outcomes of multigene testing
Results from multigene tests have several possible outcomes, including the following:[
- No variant detected.
- VUS detected.
- Pathogenic variant in a high-penetrance gene concordant with the existing personal/family history (e.g., a germline MSH2 pathogenic variant in an individual who meets Amsterdam criteria for Lynch syndrome).
- Pathogenic variant in a high-penetrance gene discordant with the existing personal/family history (e.g., a germline CDH1 pathogenic variant in an individual with no personal/family history of gastric cancer).
- Pathogenic variant in a moderate-penetrance gene (e.g., CHEK2, ATM).
- Pathogenic variant in a gene with uncertain cancer risks and/or cancer associations.
Results can also reveal more than one finding given that multiple genes are being tested simultaneously and the elevated rate of VUS.[
Considerations when using multigene testing
Using multigene panels can be complex. However, this approach may offer advantages over sequential testing strategies. For example, 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.[
However, there can be challenges when employing this testing approach. Clinical laboratories now offer a varying array of clinical cancer susceptibility gene panels.[
Providers who determine a patient's genetic testing strategy may also consider these additional challenges: the patient's out-of-pocket and overall expenses, insurance reimbursement for the genetic test, the genetic test's turn-around-time, ease of ordering the genetic test from a laboratory, the probability of identifying a VUS and managing this finding (via VUS reclassification and access to additional variant data), technical differences between genetic tests (such as the presence of a deletion /duplication assay), patient preference, and a patient's clinical history.[
Practice guidelines for optimal clinical use of multigene tests continue to evolve.[
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. For more information on moderate- and low-penetrance, see Figure 1 in Cancer Genetics Overview. 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.[
Regulation of genetic tests
Government regulation of genetic tests to date remains extremely limited in terms of both analytic and clinical validity with little interagency coordination.[
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.[
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.[
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.[
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.[
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.[
- Regulations governing clinical laboratory quality.
- Oversight of the clinical validity of genetic tests.
- The number and identification of laboratories performing genetic tests and the specific genetic tests being performed.
- Level of current knowledge about the clinical usefulness of genetic tests.
- Educational preparation in genetics of health providers, the public health community, patients, and consumers.
In October 2014, the FDA posted the notification regarding its plans to develop draft guidance on the regulation of laboratory-developed tests.[
Direct-to-Consumer (DTC) Genetic Tests
Most genetic testing for cancer and other health risks is offered by health care providers based on 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.
Genotyping for carrier status and disease risks
In 2015, the FDA provided
Genotyping for pathogenic variants inBRCA1andBRCA2
In 2023, the FDA authorized 23andMe to market a test that included 44 pathogenic variants in BRCA1 and BRCA2, including the three BRCA1 and BRCA2 founder pathogenic variants that are commonly identified in individuals of Ashkenazi Jewish descent.[
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
A potential advantage of DTC testing of these 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.
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
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, an authorized provider (e.g., primary care physician, nurse practitioner, or genetic counselor) is required to order the test.[
With respect to cancer genetic testing, there are clinical, CLIA-certified laboratories that offer multigene (panel) tests as a consumer-directed service. Factors to consider when genetic testing is ordered this way include:
- Is the test the same as what would have been ordered by the individual's own health care provider after review of personal and family history?
Multigene (panel) tests may not include all high- to moderate-risk genes in the differential, or newer/preliminary evidence genes.
- Are variants of uncertain significance (VUS) reported back to the consumer, and if so, is the individual re-contacted if the VUS is reclassified?
This is an important question to ask before testing is performed.
- What is the cost of testing?
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) for the testing to be covered. Consumer-directed testing thus eliminates the need for this requirement.
Testing for single nucleotide variants (SNVs)
DTC companies offer 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 moderately increased disease risks (usually conferring odds ratios <2.0) or modestly decreased disease risks.[
Multiple studies have found that SNV testing has not been validated as an accurate risk assessment tool. Hence, SNVs cannot replace the collection, integration, and interpretation of personal/family history risk factor information by qualified health care professionals.[
DTC whole-exome/genome sequencing and interpretation
DTC testing companies offer whole-genome sequencing (WGS) or whole-exome sequencing (WES), including SNV data. For more information about WGS and WES, see the Clinical Sequencing section in Cancer Genetics Overview. 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.[
The following are factors to consider when determining the accuracy of DTC testing and the utility of its sequence data for cancer (or other disease) risk assessment: the sequencing depth of the genes of interest, if large rearrangements or gene deletions can be detected, and if/how positive results are confirmed (e.g., through Sanger sequencing). For example, if sequencing depth is low or rare variants cannot be detected, false-negative results may be a concern. DTC testing may also call DNA sequence changes pathogenic when confirmatory testing would identify these variants as benign (false positive). When WES or WGS is performed, VUS will likely be identified,[
Considerations
There may be potential benefits associated with DTC testing. DTC marketing and provision of genetic tests may promote patient autonomy.[
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.[
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.[
Informed Consent
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.[
Inclusion of an informed consent process in counseling can facilitate patient autonomy.[
Some programs use a second informed consent process before 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.
Core elements of informed consent
Major elements of an informed consent discussion are highlighted in the preceding section. The critical elements, as described in the literature,[
- Specific test being performed.
- Elicitation and discussion of a person's expectations, beliefs, goals, and motivations.
- Explanation of how inheritance of genetic factors may affect cancer susceptibility.
- Clarification of a person's increased risk status.
- Discussion of potential benefits, risks, and limitations of testing.
- Discussion of costs and logistics of testing and follow-up.
- Discussion of possible outcomes of testing (e.g., true positive, true negative, VUS, inconclusive, false positive, false negative, secondary findings).
- Discussion of medical management options based on risk assessment and/or test results available for those who choose to test, for those who choose not to test, and for those who have positive, negative, or inconclusive results.
- Data on efficacy of methods of cancer prevention and early detection.
- Discussion of possible psychological, social, economic, and family dynamic ramifications of testing or not testing.
- Discussion of a genetic test result's implications for family members; patients may be asked to inform their family member(s) about their genetic test results.[
88 ] - Discussion of alternatives to genetic testing (e.g., tissue banking, risk assessment without genetic testing).
- Attainment of verbal and written informed consent or clarification of the decision to decline testing.
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.
Testing in children
Genetic testing for pathogenic variants in cancer susceptibility genes in children is particularly complex. While both parents [
- When screening or preventive strategies during childhood are available (e.g., MEN and FAP), testing should be encouraged on clinical grounds.
- When no risk reduction strategies are available in childhood and the probability of developing a malignancy during childhood is very low (e.g., hereditary breast/ovarian cancer syndrome), testing should not be offered.
- Some patients may be at risk of developing a malignancy during childhood without the availability of validated risk-reduction strategies (e.g., TP53 pathogenic variants). The decision to test in such circumstances is particularly controversial.[
1 ]
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.[
The consequences of genetic testing in children have been reviewed.[
In summary, genetic testing may be considered in children if the results may alter the child's medical treatment and positively impact his/her 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.[
For more information about testing children for hereditary cancer syndromes, see the following summaries:
- Genetics of Breast and Gynecologic Cancers
- Genetics of Colorectal Cancer
- Genetics of Endocrine and Neuroendocrine Neoplasias
Testing in vulnerable populations
Genetic counseling and testing require 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.[
Genetic counseling and testing in vulnerable populations raise 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.[
Providers need to assess all patients for their ability to make an uncoerced, autonomous, informed decision before 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.
Cascade Genetic Testing of Family Members
In cascade genetic testing, biological family members at risk of inheriting a familial pathogenic variant (previously identified in a relative) are offered genetic testing. The process is repeated, as additional pathogenic variant carriers are identified within a family. Cascade testing helps identify pathogenic variant carriers before cancer presentation, which allows for cancer prevention, early detection, risk reduction, and improved health outcomes.[
Uptake of cascade genetic testing
The dissemination of genetic risk information, from the proband to at-risk relatives, is essential for the uptake of cascade testing. Traditionally, this has included discussions (between the genetics provider and the proband) about the importance of relaying results to at-risk relatives in the proband's pedigree. Providers can supply the proband with a letter or educational materials to facilitate disclosure of genetic test results to family members.[
Most studies on the uptake of cascade testing were conducted in either hereditary breast and ovarian cancer (HBOC) or Lynch syndrome families. A systematic evidence review found that in HBOC families, the proband notified family members about the familial pathogenic variant 21% to 44% of the time. First-degree relatives (FDRs), females, and close family members were more likely to be informed about the familial variant. Follow-up testing rates varied depending on the study, with 15% to 57% undergoing cascade genetic testing overall.[
Barriers to cascade genetic testing
Communication barriers
Emotional barriers can influence the communication of pathogenic variant results to family members. These barriers can include the loss of a family member's contact information, the lack of a close emotional relationship with family members,[
Information interpretation
In a retrospective study on FDRs of probands with pathogenic/likely pathogenic variants, 14% of FDRs who were given information about the proband's genetic test results found the information hard to understand. FDR recall of genetic test results was concordant with the actual test result in 82% of cases. However, 10% were unable to recall the test result.[
Strategies to facilitate cascade genetic testing
Several strategies have been proposed to facilitate genetic test results disclosure and cascade testing uptake in family members. These strategies have been studied and are discussed in the following sections.
Written material
The Finland Lynch Syndrome Registry studied communicating with at-risk family members through letters. Family members (N = 446) from 36 families who had a 50% chance of having Lynch syndrome were notified about this risk via letters, which offered genetic counseling and testing for the familial variant. Of the 446 family members, 347 underwent genetic counseling, with 75% of the entire cohort (n = 334) opting for genetic testing.[
Group counseling
Establishment of the Family Information Service at Creighton University provided group counseling sessions to at-risk relatives during educational sessions. Group sizes ranged from 15 to 75 individuals. Sessions were conducted by genetic nurses and counselors at locations that were convenient for enrolled family members. While the genetic testing uptake rate was not reported, these sessions considerably reduced one-on-one health care provider time, thus increasing the capacity of the genetics clinic.[
Proband training
Some groups studied strategies that prepared probands to disseminate genetic test results to at-risk relatives. A randomized, controlled trial trained participants using a six-step communication strategy. This approach involved identifying at-risk relatives, selecting a communication method, assessing family member knowledge, sharing the genetic test result, responding to family member reactions, and providing genetic counseling resources. There were no significant differences in the genetic test result dissemination rates between intervention (n = 137) and control groups (n = 112).[
A Dutch research group explored using a two-phased telephone motivational-interview intervention conducted by five trained psychosocial workers. Consultands (n = 144) had at least one relative eligible for cascade genetic testing or cancer screening. Phase 1 determined the agenda, confirmed which family members needed to be informed by the consultand, and explored current/planned result-sharing options. Phase 2 focused on sharing certain information, building motivation and self-efficacy in the consultand, and brainstorming ways to overcome dissemination barriers. Consultands found this strategy to be feasible and acceptable. A randomized study will evaluate whether this intervention increases genetic test result dissemination.[
An Australian randomized controlled trial evaluated the impact of telephone genetic counseling in individuals who were diagnosed with genetic conditions, individuals who had children with genetic conditions, or individuals who were pathogenic variant carriers. Telephone counseling occurred 2 to 3 times (over 12 months) in the intervention group (n = 45). These individuals were compared with those in the control group (n = 50). There were no significant differences in the number of relatives seeking genetic services.[
Low- or no-cost genetic testing
One study explored free genetic testing for at-risk relatives. In a cohort of BRCA1/BRCA2 carriers (n = 115) who had relatives eligible for free family member testing, 77% of participants disclosed results to all at-risk family members. Only 60% of FDRs and 47% of more-distant relatives underwent genetic testing.[
Genetic testing laboratories are exploring ways to reduce genetic testing barriers for family members, given the low cascade testing uptake rate.[
One study performed hereditary cancer genetic testing based on solid tumor diagnoses. Testing was conducted in patients unselected for family history or national guideline–specified genetic testing. The proband's biological family members were offered no-cost genetic testing for 3 months after results were reported. At least one family member underwent genetic testing in 17.6% of eligible families. A median of two individuals per family were tested (range, 1–14 individuals), although the total number of family members eligible for testing was not reported.[
Online direct-to-consumer (DTC) testing
One DTC testing laboratory that performs a 30-gene cancer genetics panel offered reduced-cost ($50) testing to FDRs of individuals who tested positive for a pathogenic variant. Probands were emailed information about the family testing program. Those interested (n = 1,101) identified at-risk FDRs and provided their contact information. The laboratory sent emails to FDRs, inviting them to test using the same 30-gene panel (which included the pathogenic variants found in their relatives). After 1 year of follow-up, 48% of FDRs underwent genetic testing. Only 12% of FDRs who tested positive continued cascade testing of their own FDRs. Notably, 5% of FDRs had pathogenic variants in genes that differed from those found in their family members. Additionally, 16.8% of FDRs had a VUS.[
Direct provider-to-family testing
A systematic evidence review studied how genetic test results were reported to family members, using contact information provided by probands. Results showed that the number of probands tested was greater than the number of relatives who were notified about results. Four additional studies reported that relatives did not understand genetic test results. However, when these individuals were sufficiently informed by health care providers, most opted to test.[
Similarly, in a study of 30 probands with a pathogenic variant, 114 at-risk relatives were identified. Ultimately, probands gave permission for the study coordinators to contact 102 at-risk relatives. Ninety-three percent (95 of 102) of those relatives were successfully contacted by a member of the genetics team, 97% (92) agreed to genetic counseling, 86% (82) agreed to genetic testing, and 70% (66) tested for the familial pathogenic variant.[
When genetic testing is conducted in a clinical setting, there may be additional aspects to consider before contacting family members, like billing and institutional privacy regulations.
Chatbots
Chatbots use artificial intelligence to create an online avatar that can speak to users, simulating real conversations based on pre-established text-based dialogues.[
These studies reported limitations in cascade testing uptake and genetic test results dissemination when probands notified family members about genetic test results. An optimal results-sharing strategy has not been reported.[
Ethical, legal, and social issues
Ethical, legal, and social issues related to cascade genetic testing, like duty to warn and results disclosure to at-risk relatives, are discussed in the Ethical, Legal, and Social Implications section.
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