Retrospective Cohort Study on the Limitations of Direct-to-Consumer Genetic Screening in Hereditary Breast and Ovarian Cancer.

Abstract

Among cancer predisposition genes, most direct-to-consumer (DTC) genetic tests evaluate three Ashkenazi Jewish (AJ) founder mutations in <i>BRCA1/2</i>, which represent a small proportion of pathogenic or likely pathogenic variants (PLPV) in cancer predisposing genes. In this study, we investigate PLPV in <i>BRCA1/2</i> and other cancer predisposition genes that are missed by testing only AJ founder <i>BRCA1/2</i> mutations. Individuals were referred to genetic testing for personal diagnoses of breast and/or ovarian cancer (clinical cohort) or were self-referred (nonindication-based cohort). There were 348,692 participants in the clinical cohort and 7,636 participants in the nonindication-based cohort. Both cohorts were analyzed for <i>BRCA1/2</i> AJ founder mutations. Full sequence analysis was done for PLPV in <i>BRCA1/2</i>, <i>CDH1</i>, <i>PALB2</i>, <i>PTEN</i>, <i>STK11</i>, <i>TP53</i>, <i>ATM</i>, <i>BARD1</i>, <i>BRIP1</i>, <i>CHEK2</i> (truncating variants), <i>EPCAM</i>, <i>MLH1</i>, <i>MSH2/6</i>, <i>NF1</i>, <i>PMS2</i>, <i>RAD51C/D</i>, and 22 other genes. <i>BRCA1/2</i> AJ founder mutations accounted for 10.8% and 29.7% of <i>BRCA1/2</i> PLPV in the clinical and nonindication-based cohorts, respectively. AJ founder mutations accounted for 89.9% of <i>BRCA1/2</i> PLPV in those of full AJ descent, but only 69.6% of those of partial AJ descent. In total, 0.5% of all individuals had a <i>BRCA1/2</i> AJ founder variant, while 7.7% had PLPV in a high-risk breast/ovarian cancer gene. For non-AJ individuals, limiting evaluation to the AJ founder <i>BRCA1/2</i> mutations missed >90% of mutations in actionable cancer risk genes. Secondary analysis revealed a false-positive rate of 69% for PLPV outside of non-AJ <i>BRCA 1/2</i> founder mutations. DTC genetic testing misses >90% of <i>BRCA1/2</i> PLPV in individuals of non-AJ ancestry and about 10% of <i>BRCA1/2</i> PLPV among AJ individuals. There is a high false-positivity rate for non-AJ <i>BRCA 1/2</i> PLPV with DTC genetic testing.