It's easy to understand the appeal of at-home genetic testing. These direct-to-consumer (DTC) tests promise a quick, cheap, and easy alternative to clinical testing labs and a fascinating piece of modern technology. But when people use at-home genetic tests, they expect them to be accurate, and that's not always the case. In fact, a new study sheds more light on this topic, indicating that at-home testing isn't just unreliable, it may be just as likely to yield an inaccurate result as an accurate one.
One of my colleagues at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute has firsthand experience in this area. Julie Kennerly-Shah, PharmD, is Assistant Director in the Department of Pharmacy, took one of the more popular ancestry and genetic health tests and exported her test results to a third-party DNA analysis company.
She was surprised to find that her report showed she had a gene mutation linked to Lynch syndrome, a genetic condition that indicates an increased risk of colon cancer and endometrial cancer in women. The results also showed a higher risk of hypertrophic cardiomyopathy, a genetic heart disease.
Kennerly-Shah was obviously worried by the results, and she even considered changing her plans to start a family as a result of what she thought was an increased chance of endometrial cancer. Thankfully, however, she took the advice of her colleagues and scheduled an appointment with a genetic counselor at The Ohio State University Wexner Medical Center. The results were clear: she had received a false-positive test. The third-party DNA analysis company had misinterpreted her genetic test results.
Kennerly-Shah is one of millions of people to take this kind of at-home test, and she's certainly one of many to receive inaccurate results. A study published in BMJ Open Access by Exeter University researchers indicates that DTC tests are extremely unreliable and frequently lead to misleading results, largely due to the types of chips used in the test (2021; doi: https://doi.org/10.1136/bmj.n214).
The Difference Between Tests
The recent study confirms previous findings that indicate genetic tests that use single nucleotide polymorphism (SNP) chips often lead to false-positive results. A previous study used repeat medical-grade testing and sequencing technologies to find that 40 percent of findings on SNP-based tests were not present in the patient (Genet Med 2018; https://doi.org/10.1038/gim.2018.38). This study yielded similar results, showing that while SNP chips perform well for common variants, more than 65 percent of rare variants found to be present using SNP chip technology were not present in the patient using other more reliable means to test DNA such as sequencing. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the study found a positive predictive value of just 4.2 percent and found that the vast majority of variants were false positives.
The study asserts that "SNP chips are extremely poor for correctly genotyping very rare variants compared with sequencing data and that, for an individual person, a positive result for a very rare pathogenic variant is more likely to be wrong than right."
The authors of the study go on to explain that an individual rare variant is very unlikely to be present, so most results for that variant are true negatives. But because SNP chips typically assess thousands of rare variants simultaneously and have a specificity under 100 percent, false positives are bound to occur and outnumber true positives across rare variants.
"Any individual person is therefore more likely to have a false-positive result across all the rare variants than a true-positive result at that variant," the study concluded.
Why It Matters
SNP chips rely on data clustering, which works well when variants are common because a large number of data points are available. But testing becomes more difficult as the number of people with a particular genotype decreases. Most people will have the normal allele, so distinguishing a variant allele from experimental noise is extremely difficult when only a single carrier is present.
While an inaccurate test could be harmful to anyone, it's particularly risky for women whose results suggest pathogenic variants of the BRCA1 and BRCA2 genes. These direct-to-consumer tests can yield both false-positives and -negatives, and either outcome could lead to devastating results in the wrong hands.
A legitimately positive test for pathogenic variants of the BRCA1 and BRCA2 genes indicates an increased risk for several cancers, including breast and ovarian cancer.
If a doctor who isn't as well-versed in genetic research saw a positive test for one of those variants, that doctor could recommend a prophylactic hysterectomy or mastectomy based on the results. This could be a life-changing operation and opens the patient up to the inherent risks of surgery. And given the likelihood of an inaccurate test, it may be completely unnecessary.
Outside of medical treatments, a family could make major life decisions based on these outcomes. For instance, if a patient thinks a hysterectomy is likely in her future, she and her family may make the decision to try to have children earlier, thinking that urgency is necessary.
Effects for Oncologists & Patients
So how should behaviors change, given this new information? As is often the case with at-home tests, it's best to trust the word of qualified health care professionals over the results of a test you've administered yourself. At the very least, those who use a test involving an SNP chip should follow up with a genetic counselor to discuss their results.
Practicing oncologists should trust patients' genetic test results if the testing was performed in a cancer genetics clinic that uses medical-grade genetic testing with sequencing-based technologies. But even then, if the test was performed before 2013, there are genes that have been discovered to be associated with increased cancer risk for which the patient was not tested.
If an oncologist is dealing with a patient who has undergone a DTC genetic test, there's a good chance the test was SNP-based. If so, both positive and negative results should be confirmed to be accurate and a referral to a cancer genetic counselor is the best next step.
Until these at-home tests become more accurate, genetic counselors should still be the option patients turn to. Otherwise, inaccurate results and the choices that follow could lead to much more harm than good.
AMANDA TOLAND, PhD, is a member of the OSUCCC - James Molecular Carcinogenesis and Chemoprevention Program where she focuses on research to identify naturally occurring gene variation that affects cancer susceptibility, as well as mutations that drive tumors to better prevent cancers in high-risk individuals. She is Professor of Cancer Biology and Genetics at the Ohio State College of Medicine and the Co-Director of the Genomics Shared Resource.