November 12, 2019
4 min read

Direct-to-consumer genetic tests may provide false assurance to patients at risk

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Edward Esplin, MD
Edward D. Esplin

The advent of direct-to-consumer genetic testing has brought a complex science into the realm of mainstream culture, with more and more consumers using these tools to determine their ancestry and ethnicity.

According to the CDC, genealogy has become the second most popular hobby in the United States, surpassed only by gardening.

However, many direct-to-consumer (DTC) genetic test manufacturers offer “bundling” of their genealogy testing with health screenings, leading consumers to purchase and trust genetic tests of questionable validity. These limited-variant screenings generally focus on a small, specific set of genetic variants that are linked to certain diseases.

“I appreciate the level to which various DTC offerings have raised the general awareness of genetics among the general population,” Edward D. Esplin, MD, PhD, FACMG, FACP, clinical geneticist at Invitae Clinical Laboratories, said in an interview with HemOnc Today. “However, health testing is where we need to draw the line. A person should get clinical genetic testing if they are going to take any action based on the results.”

Esplin and colleagues studied two limited-variant screening tests that are authorized by the FDA. One analysis focused on a test for two MUTYH gene variants, which are linked to colorectal cancer, and another evaluated a test for BRCA1 and BRCA2.

The researchers found “alarming” rates of clinical false-negative results for both tests.

Esplin spoke with HemOnc Today about the results of his study and their potential impact on hugely popular DTC genetic testing products.

Question: What prompted you to undertake this study?

Answer: The FDA has authorized screenings for the risk for breast and colorectal cancer, and the possibility of clinical false negatives came to mind. There was no study in the literature to date that quantified the potential clinical false-negative risk associated with this kind of limited-variant screening strategy. Our goal was to quantify the risk for clinical false negatives associated with this limited-variant screening strategy that is broadly available to consumers.

Q: How did you conduct the study?

A: We looked at a data set of individuals who had undergone genetic testing and whose data were available. We knew how many had undergone testing for BRCA1 and BRCA2 and we knew how many had had a genetic variant that confers risk. Then we considered, what if these patients had first undergone one of the limited-variant screenings? How many would have been entirely missed by that strategy?


We also looked at MUTYH, which confers risk for colorectal cancer. We calculated what the clinical false-negative rate would be for those individuals had they undergone that limited-screening strategy.

Q: What were your findings?

A: We found that, as expected, the overall clinical false-negative rate for BRCA1 and BRCA2 exceeded 80%. This means that 81% of those individuals with mutated BRCA1 or BRCA2 would have been missed if they had been tested by a screening strategy limited to three variants common among individuals of Ashkenazi Jewish descent, and would have been falsely reassured.

Forty percent of individuals with mutations in both MUTYH genes would have been missed, and 22% of those who carried one MUTYH mutation would have been missed by a screening strategy limited to two variants common among individuals of northern European ancestry. Variants in both genes are associated with almost 100% lifetime risk for colorectal cancer.

Q: What is the reason for so many false negatives?

A: We describe these as “clinical false negatives” because the reason these variants aren’t detected on these screenings is because the screens aren’t looking for them.
BRCA1 and BRCA2 as two chapters of a book. Those chapters together have about 90 million letters. The variant screening offered with DTC tests is looking at three letters in that entire chapter, and nothing else. That’s where we are drawing the contrast.

That’s something important that came out of this study — it reaffirms the FDA’s recommendations. If a person undergoes DTC screening and they get a positive result or a negative result, these individuals should seek confirmatory clinical genetic testing before they take any action, even if that action is to do nothing.

Q. You also analyzed the clinical false negatives based on ethnicity. What did you find?

A: Based on the data set we had, we were able to divide the clinical false-negative results by the self-reported ethnicity. We found that not only did this limited-variant screening strategy show an alarmingly large false-negative rate, but that false-negative rate worsens based on certain ethnic backgrounds. It’s worse in self-reported Asian individuals, African Americans and those of Hispanic ancestry. This indicates that these results from limited-variant screening strategies provided a disproportionate disservice to these underrepresented populations, because they are at even higher risk for having a clinical false negative and false reassurance.


Q: Who m do you want the message of this study to reach?

A: Our intention was to publish these data and through that effort, raise awareness, not only among patients but also among clinicians. We want there to be a clear understanding that these kinds of DTC screening results should not be acted on. This study demonstrates that the DTC tests are very limited, and this limitation needs to be understood. Even the companies that make these tests acknowledge this. There are other applications for these DTC tests, and other reasons to look at genetics that are valid. However, a person who wants to know how genetics can affect their health needs to have clinical genetic testing, so they can confidently act in concert with their physician. Whether positive or negative, clinical genetic test results can lead to appropriate clinical action. – by Jennifer Byrne

For more information:

Edward D. Esplin, MD, PhD, FACMG, FACP, can be reached at 1400 16th Street, San Francisco, CA, 94103.


Esplin ED, et al. Abstract PgmNr 235. Presented at: American Society of Human Genetics Annual Meeting; Oct. 15-19, 2019; Houston.

Disclosure: Esplin reports being an employee and shareholder of Invitae Clinical Laboratories.