{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T23:01:19Z","timestamp":1789945279456,"version":"4.0.1"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Hereditary cancer testing can identify individuals with a significant risk of cancer, and provide an opportunity for early risk management, prevention, precision treatment strategies, and family cascade testing. Medical professional organizations have developed guidance on genetic testing criteria based on personal and family histories. However, many individuals with cancer-predisposing pathogenic germline variants remain unidentified. The objective of this study was to determine the utility of a multi-cancer, clinically actionable cancer syndrome gene panel in identifying pathogenic variants among individuals both meeting and not meeting national genetic testing criteria.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This retrospective cohort study analyzed 153,767 unrelated consecutive women and men, unselected for personal or family cancer history, who were referred for genetic testing across multiple sites from June 2020 to August 2023. Positivity rates were evaluated and compared according to testing guideline eligibility and cancer site-specific recommended gene sets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In a multi-cancer panel of 29 clinically actionable genes, pathogenic or likely pathogenic variants were identified in 6.5% of individuals meeting hereditary testing criteria and 4.8% of those not meeting criteria. Overall, 22% of individuals with positive findings would have been missed had guideline-informed testing criteria been used, suggesting substantial missed diagnostic and therapeutic opportunities. Gene-level analyses revealed higher positivity rates for\n                      <jats:italic>BRCA2<\/jats:italic>\n                      (met: 1.2%, not met: 0.6%),\n                      <jats:italic>BRCA1<\/jats:italic>\n                      (met: 1.0%, not met: 0.3%), and\n                      <jats:italic>ATM<\/jats:italic>\n                      (met: 0.7%, not met: 0.53%) among individuals meeting only hereditary breast and ovarian cancer criteria, and for\n                      <jats:italic>MSH2<\/jats:italic>\n                      (met: 0.9%, not met: 0.05%), and\n                      <jats:italic>MLH1<\/jats:italic>\n                      (met: 0.6%, not met: 0.04%), and\n                      <jats:italic>PMS2<\/jats:italic>\n                      (met: 0.8%, not met: 0.36%) among those meeting only Lynch syndrome criteria.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings indicate that strict testing criteria may miss 22% of individuals with an actionable hereditary cancer gene variant. The use of comprehensive multi-cancer panels, alongside broader eligibility criteria, can identify individuals with hereditary cancer syndromes and improve opportunities for targeted screening, clinical management, and cascade testing for relatives.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1924232","type":"journal-article","created":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T22:10:24Z","timestamp":1789942224000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Yield of actionable variants from high-risk cancer gene panel testing in guideline-eligible and ineligible individuals"],"prefix":"10.3389","volume":"17","author":[{"given":"Sarah S.","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, New York University Grossman School of Medicine","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Natera, Inc.","place":["Austin, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara L.","family":"Bristow","sequence":"additional","affiliation":[{"name":"Natera, Inc.","place":["Austin, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Rojahn","sequence":"additional","affiliation":[{"name":"Natera, Inc.","place":["Austin, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mia","family":"Mackall","sequence":"additional","affiliation":[{"name":"Natera, Inc.","place":["Austin, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenakshi","family":"Malhotra","sequence":"additional","affiliation":[{"name":"Natera, Inc.","place":["Austin, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youbao","family":"Sha","sequence":"additional","affiliation":[{"name":"Natera, Inc.","place":["Austin, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileen","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Natera, Inc.","place":["Austin, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivienne","family":"Souter","sequence":"additional","affiliation":[{"name":"Natera, Inc.","place":["Austin, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minetta C.","family":"Liu","sequence":"additional","affiliation":[{"name":"Natera, Inc.","place":["Austin, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam C.","family":"ElNaggar","sequence":"additional","affiliation":[{"name":"Natera, Inc.","place":["Austin, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhavana","family":"Pothuri","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, New York University Grossman School of Medicine","place":["New York, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1086\/375033","article-title":"Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies","volume":"72","author":"Antoniou","year":"2003","journal-title":"Am. 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