{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T09:59:15Z","timestamp":1784282355427,"version":"3.55.0"},"reference-count":16,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"7","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO Precision Oncology"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:sec><jats:title>PURPOSE<\/jats:title><jats:p> Among cancer predisposition genes, most direct-to-consumer (DTC) genetic tests evaluate three Ashkenazi Jewish (AJ) founder mutations in BRCA1\/2, which represent a small proportion of pathogenic or likely pathogenic variants (PLPV) in cancer predisposing genes. In this study, we investigate PLPV in BRCA1\/2 and other cancer predisposition genes that are missed by testing only AJ founder BRCA1\/2 mutations. <\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p> 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 BRCA1\/2 AJ founder mutations. Full sequence analysis was done for PLPV in BRCA1\/2, CDH1, PALB2, PTEN, STK11, TP53, ATM, BARD1, BRIP1, CHEK2 (truncating variants), EPCAM, MLH1, MSH2\/6, NF1, PMS2, RAD51C\/D, and 22 other genes. <\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p> BRCA1\/2 AJ founder mutations accounted for 10.8% and 29.7% of BRCA1\/2 PLPV in the clinical and nonindication-based cohorts, respectively. AJ founder mutations accounted for 89.9% of BRCA1\/2 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 BRCA1\/2 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 BRCA1\/2 mutations missed &gt;90% of mutations in actionable cancer risk genes. Secondary analysis revealed a false-positive rate of 69% for PLPV outside of non-AJ BRCA 1\/2 founder mutations. <\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSION<\/jats:title><jats:p> DTC genetic testing misses &gt;90% of BRCA1\/2 PLPV in individuals of non-AJ ancestry and about 10% of BRCA1\/2 PLPV among AJ individuals. There is a high false-positivity rate for non-AJ BRCA 1\/2 PLPV with DTC genetic testing. <\/jats:p><\/jats:sec>","DOI":"10.1200\/po.22.00695","type":"journal-article","created":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T19:59:41Z","timestamp":1691092781000},"update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":4,"title":["Retrospective Cohort Study on the Limitations of Direct-to-Consumer Genetic Screening in Hereditary Breast and Ovarian Cancer"],"prefix":"10.1200","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8641-0542","authenticated-orcid":false,"given":"Neelam V.","family":"Desai","sequence":"first","affiliation":[{"name":"Levine Cancer Institute, Atrium Health, Charlotte, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6082-3610","authenticated-orcid":false,"given":"Elizabeth D.","family":"Barrows","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, MedStar Georgetown University Hospital, Washington, DC"},{"name":"Georgetown University Medical Center, Lombardi Comprehensive Cancer Center, Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5916-6393","authenticated-orcid":false,"given":"Sarah M.","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Invitae Corp, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0849-7018","authenticated-orcid":false,"given":"Kathryn E.","family":"Hatchell","sequence":"additional","affiliation":[{"name":"Invitae Corp, San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1393-3590","authenticated-orcid":false,"given":"Michael J.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Invitae Corp, San Francisco, 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