DTC Genetic Tests: High Rate of False-Negative Results May Hide a Clinical Pearl

A new study is now suggesting that direct-to-consumer (DTC) genetic tests that rely on a limited variant screening approach often yield clinical false-negative results, leaving people with incomplete information.¹ The findings from the study, which were presented at the American Society of Human Genetics (ASHG) 2019 Annual Meeting, held in Houston, Texas,² showed that a clinical false-negative result can be incorrectly reassuring, and could stop people from receiving preventive care they need based on their risk.

“We wanted to provide data that quantifies how a limited screening strategy does or does not identify the information clinicians need to guide patient care. Until our paper, discussions of the limitations of the screening strategies offered via direct-to-consumer testing lacked data quantifying those limitations. We sought to provide it,” said Edward Esplin, MD, a clinical geneticist at Invitae Clinical Laboratories in San Francisco, California.

Limited variant screening tests provide information on a small specific set of genetic variants widely known to be associated with risk of a disease. However, every gene can have thousands of potential variants that are associated with disease. Currently, the US Food and Drug Administration (FDA) has approved DTC genetic screening tests for genetic risk of breast, ovarian, and colorectal cancer.

Dr Esplin and his colleagues analyzed FDA-authorized limited variant screening tests for the MUTYH gene (detects 2 variants associated with colorectal cancer common in people with northern European ancestry) and for BRCA1 and BRCA2 (detects 3 variants associated with breast cancer commonly occurring in people of Ashkenazi Jewish descent). The study included 270,806 patients who had been referred by health care providers for MUTYH genetic testing, and 119,328 who had been referred for BRCA1/2 genetic testing.

Among those referred for MUYTH genetic testing, the tests would have missed 40% of people with mutations in both MUTYH genes. In addition, 22% of carriers of mutation in one MUTYH gene would also have been missed. In the group referred for BRCA1/2 genetic testing, study results showed that approximately 19% would have received a false-negative result.

Dr Esplin’s team also analyzed the rate of false negatives among patients with different ethnic backgrounds. They found results for MUTYH genetic testing would have been clinical false-negative for 100% of Asians, 75% of blacks, 46% of Hispanics, and 33% of whites. In the group undergoing BRCA1/2 genetic testing, the numbers were similar: 98% of Asians, 99% of blacks, 94% of Hispanics, and 94% of whites would have received clinical false-negative results.

“The recommendation to not use limited screening strategy testing for clinical decision-making is well placed,” Dr Esplin said in an interview with Oncology Nurse Advisor. Variant screening strategies would have missed clinically significant genetic variants in the vast majority of patients at risk for breast and colorectal cancer. These results underscore the need to use comprehensive clinical genetic testing results for any health decisions, he added.