Rachel Horton, BA, BMBCh, MSc, clinical training fellow, clinical ethics and law within medicine at the University of Southampton in the U.K., also isn’t surprised by Invitae’s results. However, she said, “I would imagine a lot of people who’ve bought these sorts of tests might be surprised by the [results].”

Horton noted that DTC genetic testing companies are explicit that they only test for a limited number of variants. In the case of 23andMe’s BRCA1/2 test, for instance, the company cautions on its website that “more than 1000 variants in the BRCA1 and BRCA2 genes are known to increase cancer risk. Our report only includes 3 of those variants.”

As such, 23andMe rejects the notion that it “delivers ‘false negatives’ for genetic variants that it does not claim to test for,” a spokesperson for the company wrote to Cancer Therapy Advisor in response to its competitor’s research.

Continue Reading

Related Articles

The spokesperson stressed that the company’s test is not a diagnostic test. However, it can help identify risk in individuals who don’t meet clinical screening guidelines, citing research suggesting that 50% of families found to have BRCA1/2 mutations had no prior familial history of ovarian or breast cancer that would have qualified them for clinical screening.2

In addition, 23andMe has conducted “extensive user comprehension testing” to assure its customers understand that their DNA tests don’t screen for all genetic variants linked to a given disease as part of its authorization with the FDA; the spokesperson added that according to their user surveys, 100% of customers understood that receiving a “0 variant” result from the microarray test doesn’t mean that there can’t be other potential disease-causing variants in their genome.

Nevertheless, Horton warned that customers may not read all the fine print associated with their test results from DTC genetic-testing firms. “Based on clinical experience, we know that quite a lot of people seem to expect that a BRCA test, for example, [is] a yes/no test that checks if you’ve got the BRCA ‘gene’ — and if you think it’s that kind of test, then are you really going to read all the information around your reassuring results?”

It is conceivable that individuals with a family history of cancer could be mistakenly reassured by a negative result from a DTC genetic test and on that basis, decide that visiting a clinician is unwarranted, Horton said, who along with colleagues recently published a paper providing guidance for clinicians on advising patients on DTC genetic tests.3

In addition to the issue of perceived “false negative” results from DTC genetic tests, there is also evidence that false positives can occur.4 SNP microarrays, though good at detecting common variants, can mistakenly produce false positives for rare variants. DTC genetic testing companies typically only report the few variants their arrays are good at detecting accurately and will omit any incorrect results in their report.

However, several companies allow customers to download their raw genetic data, and when this is uploaded to third-party platforms that advertise more extensive genetic analyses, the false positives could be recognized as disease-causing variants.

Horton noted anecdotal cases of individuals being referred to clinical geneticists after receiving such false positives, where comprehensive genetic testing revealed that the supposed disease-causing variant wasn’t in the patients’ genome.

Ultimately, “it really comes down to clearly explaining to customers what they do get and what they don’t get. That’s the part that I think we really have to focus on,” Ramos said. “If you’re somebody who is concerned about your breast cancer family history, then [genetic analysis] does need to be [conducted through] sequencing.”


  1. Esplin ED, Haverfield E, Yang S, et al. Limitations of direct-to-consumer genetic screening for hereditary breast, ovarian, and colorectal cancer risk. Presented at: 2019 American Society of Human Genetics (ASHG) Annual Meeting; October 17; Houston, TX. Abstract PgmNr235.
  2. King M, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award [published online September 17, 2014]. JAMA, doi: 10.1001/jama.2014.12483
  3. Horton R, Crawford G, Freeman L, et al. Direct-to-consumer genetic testing [published online October 16, 2019]. BMJ, 2019;367:I5688 doi: 10.1136/bmj.l5688
  4. Weedon MN, Jackson L, Harrison JW, et al. Very rare pathogenic genetic variants detected by SNP-chips are usually false positives: implications for direct-to-consumer genetic testing. BioRxiv. doi: 10.1101/696799