The last few years have seen millions of people sending saliva samples to private companies for DNA analysis to better understand their risks of developing disease. Yet such direct-to-consumer (DTC) genetic tests are limited in scope, and typically only interrogate for a few well-studied disease-causing variants.

A new study estimated how likely such tests are to miss pathogenic variants and found that if only DTC testing were undertaken, an overwhelming majority of people would receive clinical “false-negative results” for mutations associated with breast, ovarian, and colorectal cancer.

Results varied across ethnic groups; in some, the chance of missing a disease-causing variant could be as high as 100%.

The research was conducted by Invitae, a California-based medical genetic testing company, which presented results of the study at the annual meeting of the American Society of Human Genetics in late 2019.1

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“We did expect there to be … some clinical ‘false-negative rate,’ [but] I was honestly surprised that it was as high as it was,” Edward Esplin, MD, PhD, clinical geneticist at Invitae, told Cancer Therapy Advisor. Dr Esplin expressed concern that consumers may not understand the limited scope of DTC genetic tests and take their results to mean that they are free of risky mutations, as well as be mistakenly reassured by negative results.

DTC genetic tests typically use microarrays to search for specific genetic variants with a strong association with disease. 23andMe’s FDA-approved BRCA test, for instance, is designed to detect 3 well-studied mutations within the BRCA1 and BRCA2 genes that are common in people of Ashkenazi Jewish descent, but are rare among other ethnicities. In January 2019, the FDA also gave 23andMe the green light to market a test for 2 variants in the MUTYH gene that are known to be linked to the hereditary colorectal cancer syndrome MUTYH-associated polyposis. Those variants are most common in people of Northern European descent.

To better understand how often these tests would miss other disease-causing DNA variants, Dr Esplin and his colleagues examined 2 cohorts that had been referred by their health care providers to Invitae for comprehensive genetic testing for cancer-causing variants: 1 cohort of more than 270,000 patients with a personal or family history of any cancer who received screening for the MUTYH gene; and 1 cohort of nearly 120,000 patients with a personal or family history of ovarian or breast cancer who received BRCA1/2 screening.

After sequencing the relevant genes in each cohort to identify pathogenic mutations, the researchers investigated how many patients had only the particular variants targeted by common DTC genetic tests.

Of 5929 patients in the first cohort who had at least one pathogenic or likely pathogenic variant in the MUTYH gene, only 4552 had 1 of the 2 specific variants that would be detected by DTC tests. Overall, the researchers calculated that if patients had only received DTC genetic testing, 40% of people with mutations in both copies of the MUTYH gene would have been missed. In other words, some individuals with 2 pathogenic or likely pathogenic variants in MUTYH — a situation which confers a nearly 100% lifetime risk of developing colon cancer — would not have been identified using the DTC limited-variant strategy.