Clinical confirmation of consumer genomic test results
The landscape of consumer genomic testing is changing rapidly. These tests are highly variable in the methods employed, the information provided and the regulation of the lab doing the testing. Some results have the potential to impact patient care, and such results may or may not require clinical confirmation.
Clinical confirmation may be needed when:
- Results may impact patient care
- A healthcare provider was not involved in ordering the test
- SNP-based microarray testing was used
- Variant interpretation is unclear, or does not follow accepted guidelines
- Results are from a direct-to-consumer (DTC) test
- Regulatory agencies issue specific guidance
This resource discusses these factors in more detail to help determine if clinical confirmation is indicated after consumer genomic testing. As always, use clinical judgement based on the patient’s personal and familial risk factors when assessing for a hereditary condition, and consult with a healthcare provider with expertise in genetics as needed.
Results may impact patient care
Consumer genomic tests report on a wide range of variants, which may include:
- Rare, high risk syndromes (Hereditary Breast and Ovarian Cancer)
- Common, complex diseases (diabetes)
- Carrier status (sickle cell disease)
- Pharmacogenomic information (cytochrome P450)
- Wellness information (recommended diet and exercise plans)
- Entertainment (taste preferences, curly hair)
When a risk for a medical condition is reported, further interpretation is often needed to determine if the result has clinical significance.
- Some tests include variants that are not strongly associated with the condition and have limited impact on overall disease risk (clinical validity)
- Some variants included in a risk assessment are strongly associated with a condition but may not impact the specific individual’s medical care (clinical utility)
Clinicians should determine whether the variant identified is in a gene that has well-established gene-disease risk correlation and has well-understood clinical implications that are relevant to the patient, as noted above. While consumer-driven test results are often advertised as “actionable” or “clinical grade,” there is no consensus on what these terms actually signify. See the Resources below for help determining what genes may be medically actionable.
Involvement of a healthcare provider
Recognizing that a test was obtained without the involvement of a healthcare provider provides a clue that the test used a technology that is not considered diagnostic, or that the lab is regulated in such a way that its results are not to be used in making management decisions. If a lab employs or contracts with a clinician to facilitate consumer-driven tests, their level of involvement can vary greatly. Some labs recommend clinical confirmation, even when the test was facilitated by a healthcare provider.
Test methods used
Clinical confirmation is indicated for variants detected by single nucleotide polymorphisms (SNP)-based microarray. Some consumer genomic tests, such as DTC testing, use this method to identify the presence or absence of specific variants of interest. This technology can have a high rate of false negatives or false positives compared to testing methods used for clinical diagnosis.
Clinical confirmation is not typically indicated for variants detected by next-generation sequencing (NGS). NGS is the most common technology used in clinician-ordered genomic testing and is also employed in some consumer genomic testing.
At a reputable diagnostic laboratory, the analytic validity of NGS is generally high, and confirmation of a positive result by another lab is usually not needed.
Data interpretation methods used
Variant interpretation & classification
In addition to the variant detection methods used (SNP-based microarray versus NGS), the methods used to interpret variants are important to ensure the result is accurate.
Labs should follow the American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines for interpretation of variants as pathogenic, benign, etc. Interpretation of results should come from multiple lines of evidence, using data from population, computational, functional or segregation studies.
If in doubt about whether a particular result may be used for clinical purposes, refer to the test report, as the company should indicate this. Additionally, consultation with a genetic expert may also be helpful when results are from a less experienced laboratory, in particular those without board-certified geneticists on staff.
Third-party analysis of raw genomic data
Some labs provide raw data to the consumer, which can be interpreted by third parties (a service separate from the consumer and the lab utilized). Third party interpretation has been shown to be inaccurate, sometimes to a great extent, due to factors such as the absence of bioinformatic variant filtration or a lack of validation of results. This can result in false positives and false negatives. Third party interpretation companies that use a wiki knowledge base may also provide inaccurate information about the association between a given gene or variant and disease. This may lead the consumer towards unnecessary screening or interventions that are not evidence-based.
If a patient learns of a variant of suspected clinical interest identified through third party analysis, this result should be clinically confirmed before making any medical decisions.
How test was accessed
However a test was accessed, consumer genomic test reports may include a disclaimer that the result is not to be used for medical management. This information may also be available on the company’s website. In these cases, clinical confirmation of potentially actionable results is indicated.
DTC genetic tests are tests that the consumer obtains directly from the testing company without the involvement of a clinician in ordering or interpreting results.
DTC tests typically use genotyping with SNP microarrays, although there are some companies using NGS as well. DTC tests are generally not considered to be a comprehensive analysis and variants reported by the company, or through third party services, are not to be used for medical decision-making without confirmation.
Consumer-driven and other approaches
Consumer-driven tests are facilitated by a healthcare provider through the testing company. The ordering physician may have a financial relationship with the company and limited interaction with the patient. If this is the case, then there is little or no discussion of the patient’s medical history. Genetic counseling services may also be provided to help consumers understand their results.
Consumers may also have genomic testing through an employer wellness program or a large healthcare system-based genomic research project. Clinical confirmation may or may not be indicated in these scenarios, depending on the test parameters and lab recommendations.
Genomic tests ordered by a patient’s healthcare provider in the traditional model of clinical care typically do not need to be confirmed, unless one of the other criteria above is met (e.g., SNP-based assay without appropriate validation methods).
DTC tests are marketed directly to the public. As a result, the FDA has taken an active role in regulation of these tests.
As of this writing:
- The FDA restricts DTC companies from marketing their products as diagnostic tests.
- The FDA has determined that DTC tests should not be used for medical decision-making.
- The FDA uses its discretion and currently does not regulate consumer-driven tests, such as consumer-driven NGS tests facilitated by the company’s provider.
Regulation of genetic tests is complex and involves many agencies, such as FDA, CLIA and CAP. If unsure whether regulation impacts use of results for management, check with the lab.
Coordinating confirmatory testing
If confirmatory testing is indicated:
- Obtain a targeted personal and family history for the condition in question.
- Determine if testing will be limited to confirming the variant(s) reported by consumer genomic test or whether broader testing is indicated, such as a panel of genes related to the condition of interest.
- Provide information about the benefits and limitations of testing and the implications of possible results for the patient.
- Enlist a health professional with expertise in genetics as needed to assist in the process.
FDA: Food and Drug Administration. DTC tests providing medical information are reviewed to determine validity of test claims and whether information provided is easily understood without the aid of a healthcare provider.
CLIA: Clinical Laboratory Improvements Amendments of 1988. CLIA certification ensures test results are meeting industry standards.
CAP: College of American Pathologists. Labs that are CAP accredited meet a core set of requirements.
Consumer genomic testing: Genetic testing accessed by individuals independent of their own healthcare provider.
Direct-to-consumer testing: Genetic tests are tests that the consumer obtains directly from the testing company without the involvement of a clinician in ordering or interpreting results.
Consumer-driven testing: Initiated by the individual and facilitated by a healthcare provider through the testing company.
Provider-ordered testing: The conventional method of genetic testing, where the patient consults with their own healthcare provider or is referred to a genetic specialist for genetic counseling and testing.
SNP-based microarray testing: Also called genotyping, this technology examines hundreds to thousands of small changes (single nucleotide polymorphisms) in a person’s genomic information. Information provided is primarily based on association studies.
Next-generation sequencing (NGS): Technology used in analyzing single variants, genes, the exome (coding regions of the genome) or the whole genome.
Recommendations for reporting of secondary findings (ACMG). Lists genes that have management guidelines when detected as a secondary finding in genetic testing.
GeneReviews (NCBI). Provides clinically relevant and medically actionable information for inherited conditions.
MedlinePlus/Genetics Home Reference (National Library of Medicine). Provides signs and symptoms, genetic cause, and inheritance pattern of various health conditions.
Accessing Genetic Services (JAX). Lists tools and websites to help find genetic professionals and communicate with patients about a genetics referral.
Genetic Testing Methods (JAX). Provides information about indications for use of different test methods.
Informed Consent and Pretest Counseling Checklist (JAX). Lists the key points to communicate in informed consent.
Single Nucleotide Polymorphisms (NHGRI). Describes and provides examples of single nucleotide polymorphisms, or SNPs.
American College of Medical Genetics and Genomics. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement. Genet Med. 2016; 19(2):249-255.
American College of Medical Genetics and Genomics Board of Directors. The use of ACMG secondary findings recommendations for general population screening: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2019; 21(7):1467-1468.
Kilbride, M. K., Domchek, S. M., & Bradbury, A. R. (2019). How Should Patients and Providers Interpret the US Food and Drug Administration's Regulatory Language for Direct-to-Consumer Genetic Tests? J.Clin Oncol. 37(28), 2514–2517.
Tandy-Connor S, Guiltinan J, Krempely K, et al. False-positive results released by direct-to-consumer genetic tests highlight the importance of clinical confirmation testing for appropriate patient care. Genet Med. 2018; 20(12):1515-1521.
US Food and Drug Administration (2019, December 20). Direct-to-Consumer Tests.Accessed January 7, 2021.
US Food and Drug Administration (2018, April). Evaluation of automatic class III designation for 23andMe Personal Genome Service Genetic Health Risk Report for BRCA1/BRCA2 (selected variants): Decision Summary. Accessed January 7, 2021.