Study: Evaluation of some direct-to-consumer genetic testing reveals inaccuracies and misinterpretations
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Direct-to-consumer (DTC) tests, as the name implies, are genetic tests that a consumer can request directly from a company without involving a doctor or healthcare professional. DTC genetic tests are available for looking at common traits, making health predictions (e.g. presence of particular mutations for cystic fibrosis or sickle cell disease) and for ancestry analysis. In all cases, confirmation of any results by a clinical laboratory is needed to ensure that information is correct before any medical conclusions are possible.
More recently DTC genetic tests for determination of the presence of the 3 Jewish founder mutations in and have been made available. Note, this study evaluated DTC genetic tests that were done before 23andMe's more recently approved DTC test for the 3 common Jewish founder mutations was available. The quality of the test for the 3 common Jewish founder mutations was evaluated and approved by the .
This study highlights the need for clinical validation of DTC genetic testing to confirm results and to ensure appropriate interpretation of results.
This study is about:
A clinical laboratory's evaluation of direct-to-consumer (DTC) tests and associated raw data analysis.
The allows direct-to-consumer genetic testing for ancestry analysis, raw data, and limited clinical testing (including the 3 common Jewish mutations). These genetic tests come with a clear warning that any potential clinical variants must be reconfirmed by testing in a clinical laboratory.
Researchers at Ambry Genetics, a private clinical testing laboratory found that many mutations reported by DTC testing were absent () or misinterpreted.
- 40% of mutations (17 of 43) identified by DTC or subsequent third-party analysis of raw data were false positives: testing new samples showed that the individuals involved did not carry these mutations.
- Among mutations present, 8 that were classified as having "increased risk” by DTC or third-party providers were known to be benign, common variants or of unknown significance.
We note that this study predated the recent approval of DTC testing for 3 common Jewish mutations in and (see prior XRAYS review). DTC testing for the 3 common Jewish mutations has met standards for accuracy and reliability; these tests were correct and were not the type of tests examined by this study. Some DTC genetic tests (e.g. ancestry analysis) provided consumers with whole genome raw data. This raw data includes sequence from regions that may have poor sequence quality or insufficient information. These regions would not be appropriate to determine presence or absence of a mutation (and are therefore not intended for clinical use).
What does this mean for me?
If you have had or are considering DTC genetic testing, be aware that the information provided is not intended for clinical diagnosis or risk assessment. All potential mutations found via DTC testing need to be reconfirmed by a clinical diagnostic laboratory. This study highlights the high potential rate of false positives—DTC results that incorrectly stated that individuals carried a mutation when they did not. These erroneous results can be a technical limitation of the DTC tests and analysis of raw data. Tests to reconfirm the presence or absence of these mutations are needed before this information can be used for clinical decisions.
The misinterpretation of some mutations as "increased risk" rather than benign mutations, which frequently occur in the population and are not associated with disease risk, points to the need for adequate genetic counseling from a certified genetic counselor or other trained health care professional.
It is important to know that DTC testing is typically not comprehensive. It may include only some and not all genes for a disease, and it may not test for some mutations in all regions of individual genes. Clinical laboratory testing is more comprehensive for a given disease or gene tested. FORCE recommends consulting a genetics professional (such as a board certified genetic counselor, medical geneticist or other provider with advanced training in medical genetics) before and after being tested so that the appropriate test is performed and properly evaluated. If DTC testing is pursued, it is important to bring any test results to your health care provider so you can discuss what you have or have not had tested and to ensure a complete understanding of your genetic tests.
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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. 2018.Genetics in Medicine. Advanced online publication March 22, 2018. doi: 10.1038/gim.2018.38.
FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.
This article is relevant for:
People who are considering or have had direct-to-consumer testing
This article is also relevant for:
people with breast cancer
men with breast cancer
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IN-DEPTH REVIEW OF RESEARCH
The allows direct-to-consumer genetic testing for an individual’s ancestry analysis and non-disease status. These genetic tests come with clear warning that any potential clinical variants identified must be reconfirmed by testing in a clinical laboratory. However, people who have DTC testing to look at ancestry or other non-clinical purposes can obtain their raw genetic sequence. The caveat is that raw genetic sequenced may be unprocessed, without quality validation for many reported regions. There are third party companies that will interpret this information for a fee. However, the quality of sequence or the method of testing (such as single nucleotide polymorphisms or testing) may not be suitable for analysis. This can leave consumers with the false impression that the information is accurate and known.
Researchers of this study wanted to know:
How DTC results compared to confirmation test results from their clinical laboratory. In particular, they wanted to determine the percentage of DTC results that were confirmed, and whether the variant classification matched that of the DTC testing company or third-party service.
Populations looked at in this study:
Researchers examined 49 cases that had been submitted for testing; each case was retrospectively identified as having prior DTC testing. The majority of these cases were from females (92%), unaffected with disease at time of testing (74%), 30-49 years old (53%), and Caucasian (51%).
This study from Genetics in Medicine in March 2018 involved 49 cases of DTC genetic tests that were tested at Ambry Genetics, a private clinical testing laboratory, to confirm or refute DTC results. Researchers found many mutations reported by DTC testing that were absent on Ambry's test () or misinterpreted.
- 40% of mutations identified (N=43) by DTC were false positives; testing new samples showed that the individuals did not carry the reported mutations.
- 26 of 43 mutations (60%) were confirmed to be correctly identified, including 2 in , 13 in or , including the 3 founder mutations and 4 unique mutations.
- 17 of 43 mutations (40%) were confirmed to be incorrectly identified, including 3 in , 5 in , 2 in , 1 in TP3, 1 in and 2 in .
- 8 mutations that DTC or third-party providers classified as having "increased risk" were mutations that are known to be benign, common variants or of unknown significance.
- These included 1 mutation each in , and that experts classify as benign and occur frequently in the general population.
This study was limited to DTC cases referred to Ambry Genetics for clinical testing. In these cases, the consumer/patient and health care provider had chosen to confirm DTC testing, which may introduce some bias into the sample selection. The study authors acknowledge that the sample size is small (N=49), and they are collecting a larger series of cases to confirm these results. Confirmation by other clinical laboratories is needed to ensure that these results are generalizable. A further limitation is that only genetic testing for genes that Ambry currently evaluates were tested; only a subset of genes was evaluated.
An additional limitation is that this study does not evaluate false negatives in DTC testing - patients who received a result indicating that they had no mutations in particular genes who actually have a mutation present. Individuals whose results indicate no mutations that increase risk are unlikely to follow-up with clinical laboratory testing. Researchers did not report evaluating any cases of this type.
Because DTC testing is not designed to be used for clinical purposes, all DTC tests need to be confirmed by clinical laboratory testing. The presence of a DTC-identified mutation must be confirmed to rule out a result. Misinterpretation of the clinical significance of particular mutations by DTC companies or third-party entities has occurred. Consumers are advised to consult a genetic counselor or informed health care provider to determine the most appropriate test given their situation and to evaluate their genetic test results. DTC testing may (often) not be comprehensive; absence of mutations in a DTC test may not rule out the presence of a mutation in all genes or all gene regions associated with hereditary breast cancer or other hereditary diseases.
NCCN guidelines recommend genetic counseling and testing for people without cancer who have the following family history:
- A relative who has tested positive for an in a gene that increases cancer risk.
- One or more first- or second-degree relatives with breast cancer and any of the following:
- diagnosed at age 45 or younger
- two separate breast cancers, with the first diagnosis at age 50 or younger
- male breast cancer
- One or more first- or second-degree relatives with:
- colorectal cancer before age 50
- endometrial cancer before age 50
- ovarian, , primary peritoneal cancer
- rare or childhood cancers
- One or more first-degree relatives with:
- or high-grade cancer
- pancreatic cancer
- Two or more relatives on the same side of the family diagnosed with any combination of the following at any age:
- breast cancer
- pancreatic cancer
- adrenal cancer
- brain tumors
- endometrial cancer
- thyroid cancer
- kidney cancer
- diffuse gastric cancer
- colon cancer
- Is genetic testing warranted for me, given my personal and family history?
- If testing is appropriate, what is the most appropriate and useful genetic test for me given my own medical history and my family history?
- How do I get confirmation testing for mutations found by a DTC test?
- How can I get a referral to a certified genetic counselor to discuss my genetic test results?
- Are the mutations found in my DTC test likely benign, pathogenic or of unknown significance? What follow-up is recommended?
Below are clinical trials that include genetic counseling and testing.
- NCT02665195: Registry Of MultiPlex Testing (PROMPT). PROMPT is an online research registry. The goal of PROMPT is to help researchers to better understand the risks that are linked to mutations in less well-studied genes.
- NCT02620852: WISDOM Study: Women Informed to Screen Depending on Measures of Risk offers women age 40-74 the opportunity to undergo risk assessment and genetic testing in order to determine the best breast screening options based on their situation.
- NCT04476654: Improving Uptake of Genetic Cancer Risk Assessment in African American Women-Video. This study looks at the usefulness of intervention with a culturally-tailored video to improve uptake of genetic counseling in Black women who are at increased risk of .
- NCT05694559: Connecting Black Families in Houston, Texas to Genetic Counseling, Genetic Testing, and Cascade Testing by Using a Simple Genetic Risk Screening Tool and Telegenetics. This study will provide genetic testing to 150 Black individuals and families and provide genetic counseling and risk reduction resources to individuals with a mutation linked to increased cancer risk.
Other genetic counseling or testing studies may be found here.
FORCE offers many peer support programs for people with inherited mutations.
- Our Message Boards allow people to connect with others who share their situation. Once registered, you can post on the Diagnosed With Cancer board to connect with other people who have been diagnosed.
- Our Peer Navigation Program will match you with a volunteer who shares your mutation and situation.
- Our moderated, private Facebook group allows you to connect with other community members 24/7.
- Check out our virtual and in-person support meeting calendar.
- Join one of our Zoom community group meetings.
The following resources can help you locate a genetics expert near you or via telehealth.
Finding genetics experts
- The National Society of Genetic Counselor website has a search tool for finding a genetic counselor by specialty and location or via telehealth.
- InformedDNA is a network of board-certified genetic counselors providing this service by telephone. They can also help you find a qualified expert in your area for face-to-face genetic counseling if that is your preference.
- Gene-Screen is a third party genetic counseling group that can help educate, support and order testing for patients and their families.
- JScreen is a national program based out of Emory University that provides low-cost at-home genetic counseling and testing with financial assistance available.
- Grey Genetics provides access to genetic counselors who offer genetic counseling by telephone.
- The Genetic Support Foundation offers genetic counseling with board-certified genetic counselors.
- The American College of Medical Genetics website has a tool to find genetics clinics by location and specialty.
Other ways to find experts
- Register for the FORCE Message Boards and post on the Find a Specialist board to connect with other people who share your situation.
- The National Cancer Institute (NCI)-designated comprehensive cancer centers have genetic counselors who specialize in cancer.
- FORCE's toll-free helpline at: 866-288-RISK, ext. 704 will connect you with a volunteer board-certified genetic counselor who can help you find a genetics expert near you.
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