{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:19:53Z","timestamp":1787066393556,"version":"build-2736575974"},"reference-count":33,"publisher":"BMJ","issue":"4","funder":[{"name":"prevent breast cancer","award":["GA19-002"],"award-info":[{"award-number":["GA19-002"]}]},{"DOI":"10.13039\/100014653","name":"Manchester NIHR Biomedical Research Centre","doi-asserted-by":"crossref","award":["IS-BRC-1215-20007"],"award-info":[{"award-number":["IS-BRC-1215-20007"]}],"id":[{"id":"10.13039\/100014653","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,11,14]]},"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The identification of germline pathogenic gene variants (PGVs) in triple negative breast cancer (TNBC) is important to inform further primary cancer risk reduction and TNBC treatment strategies. We therefore investigated the contribution of breast cancer associated PGVs to familial and isolated invasive TNBC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Outcomes of germline\n                      <jats:italic>BRCA1<\/jats:italic>\n                      ,\n                      <jats:italic>BRCA2<\/jats:italic>\n                      and\n                      <jats:italic>CHEK2<\/jats:italic>\n                      _c.1100delC testing were recorded in 1514\u2009women (743\u2014isolated, 771\u2014familial), and for\n                      <jats:italic>PALB2<\/jats:italic>\n                      in 846\u2009women (541\u2014isolated, 305\u2014familial), with TNBC and smaller numbers for additional genes. Breast cancer free controls were identified from Predicting Risk Of Cancer At Screening and BRIDGES (Breast cancer RIsk after Diagnostic GEne Sequencing) studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>BRCA1<\/jats:italic>\n                      _PGVs were detected in 52 isolated (7.0%) and 195 (25.3%) familial cases (isolated\u2014OR=58.9, 95%\u2009CI: 16.6 to 247.0),\n                      <jats:italic>BRCA2<\/jats:italic>\n                      _PGVs in 21 (2.8%) isolated and 67 (8.7%) familial cases (isolated\u2014OR=5.0, 95%\u2009CI: 2.3 to 11.2),\n                      <jats:italic>PALB2_<\/jats:italic>\n                      PGVs in 9 (1.7%) isolated and 12 (3.9%) familial cases (isolated\u2014OR=8.8, 95% CI: 2.5 to 30.4) and\n                      <jats:italic>CHEK2_c<\/jats:italic>\n                      .1100delC in 0 isolated and 3 (0.45%) familial cases (isolated\u2014OR=0.0, 95%\u2009CI: 0.00 to 2.11).\n                      <jats:italic>BRCA1<\/jats:italic>\n                      _PGV detection rate was &gt;10% for all familial TNBC age groups and significantly higher for younger diagnoses (familial: &lt;50 years, n=165\/538 (30.7%); \u226550 years, n=30\/233 (12.9%); p&lt;0.0001). Women with a G3_TNBC were more likely to have a\n                      <jats:italic>BRCA1_<\/jats:italic>\n                      PGV as compared with a\n                      <jats:italic>BRCA2<\/jats:italic>\n                      or\n                      <jats:italic>PALB2<\/jats:italic>\n                      _PGV (p&lt;0.0001). 0\/743 isolated TNBC had the\n                      <jats:italic>CHEK2_<\/jats:italic>\n                      c.1100delC PGV and 0\/305 any\n                      <jats:italic>ATM<\/jats:italic>\n                      _PGV, but 2\/240 (0.83%) had a\n                      <jats:italic>RAD51D<\/jats:italic>\n                      _PGV.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      PGVs in\n                      <jats:italic>BRCA1<\/jats:italic>\n                      are associated with G3_TNBCs. Familial TNBCs and isolated TNBCs &lt;30 years have a &gt;10% likelihood of a PGV in\n                      <jats:italic>BRCA1. BRCA1<\/jats:italic>\n                      _PGVs are associated with younger age of familial TNBC. There was no evidence for any increased risk of TNBC with\n                      <jats:italic>CHEK2<\/jats:italic>\n                      or\n                      <jats:italic>ATM<\/jats:italic>\n                      PGVs.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2023-109671","type":"journal-article","created":{"date-parts":[[2023,12,16]],"date-time":"2023-12-16T13:20:13Z","timestamp":1702732813000},"page":"385-391","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["Germline testing of\n                    <i>BRCA1<\/i>\n                    ,\n                    <i>BRCA2<\/i>\n                    ,\n                    <i>PALB2<\/i>\n                    and\n                    <i>CHEK2<\/i>\n                    c.1100delC in 1514 triple negative familial and isolated breast cancers from a single centre, with extended testing of\n                    <i>ATM<\/i>\n                    ,\n                    <i>RAD51C<\/i>\n                    and\n                    <i>RAD51D<\/i>\n                    in over 400"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6297-2855","authenticated-orcid":false,"given":"Emma R","family":"Woodward","sequence":"first","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK"},{"name":"Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK"},{"name":"Manchester Breast Centre, The Christie NHS Foundation Trust, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Lalloo","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8035-4471","authenticated-orcid":false,"given":"Claire","family":"Forde","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Pugh","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9360-8194","authenticated-orcid":false,"given":"George J","family":"Burghel","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene","family":"Schlecht","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6625-7739","authenticated-orcid":false,"given":"Elaine F","family":"Harkness","sequence":"additional","affiliation":[{"name":"Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Howell","sequence":"additional","affiliation":[{"name":"Manchester Breast Centre, The Christie NHS Foundation Trust, Manchester, UK"},{"name":"Prevent Breast Cancer Unit, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK"},{"name":"Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sacha J","family":"Howell","sequence":"additional","affiliation":[{"name":"Manchester Breast Centre, The Christie NHS Foundation Trust, Manchester, UK"},{"name":"Prevent Breast Cancer Unit, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK"},{"name":"Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7264-6201","authenticated-orcid":false,"given":"Ashu","family":"Gandhi","sequence":"additional","affiliation":[{"name":"Prevent Breast Cancer Unit, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK"},{"name":"Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D Gareth","family":"Evans","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK"},{"name":"Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK"},{"name":"Manchester Breast Centre, The Christie NHS Foundation Trust, Manchester, UK"},{"name":"Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,12,16]]},"reference":[{"key":"2025101710550292000_61.4.385.1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-3045"},{"key":"2025101710550292000_61.4.385.2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mds187"},{"key":"2025101710550292000_61.4.385.3","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djaa023"},{"key":"2025101710550292000_61.4.385.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2005936"},{"key":"2025101710550292000_61.4.385.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0009-7"},{"key":"2025101710550292000_61.4.385.6","doi-asserted-by":"publisher","DOI":"10.1038\/nature10760"},{"key":"2025101710550292000_61.4.385.7","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-1415"},{"key":"2025101710550292000_61.4.385.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-021-01011-8"},{"key":"2025101710550292000_61.4.385.9","unstructured":"Available: https:\/\/www.england.nhs.uk\/wp-content\/uploads\/2018\/08\/Rare-and-inherited-disease-eligibility-criteria-version-5.2.pdf [Accessed 01 Oct 2023]."},{"key":"2025101710550292000_61.4.385.10","unstructured":"Available: https:\/\/www.nccn.org\/guidelines\/guidelines-detail?category=2&id=1503 [Accessed 21 Aug 2023]."},{"key":"2025101710550292000_61.4.385.11","doi-asserted-by":"crossref","DOI":"10.3390\/cancers12123697","article-title":"Long-term evaluation of women referred to a breast cancer family history clinic","volume":"12","author":"Howell","year":"2020","journal-title":"Cancers (Basel)"},{"key":"2025101710550292000_61.4.385.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2022.03.009"},{"key":"2025101710550292000_61.4.385.13","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1913948"},{"key":"2025101710550292000_61.4.385.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01234-6"},{"key":"2025101710550292000_61.4.385.15","unstructured":"Available: https:\/\/www.mrcholland.com\/products\/33815\/Product%20description%20P045-D1%20BRCA2-CHEK2-v05.pdf [Accessed 20 Sep 2023]."},{"key":"2025101710550292000_61.4.385.16","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2025101710550292000_61.4.385.17","doi-asserted-by":"publisher","DOI":"10.1007\/s10689-011-9506-2"},{"key":"2025101710550292000_61.4.385.18","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.067850"},{"key":"2025101710550292000_61.4.385.19","unstructured":"Available: https:\/\/www.engage.england.nhs.uk\/consultation\/specialised-services-consultation\/user_uploads\/brca-policy.pdf [Accessed 27 Aug 2023]."},{"key":"2025101710550292000_61.4.385.20","unstructured":"Available: https:\/\/www.nice.org.uk\/guidance\/cg164\/documents\/short-version-of-addendum [Accessed 27 Aug 2023]."},{"key":"2025101710550292000_61.4.385.21","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.7112"},{"key":"2025101710550292000_61.4.385.22","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.19.01907"},{"key":"2025101710550292000_61.4.385.23","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0000000000003459"},{"key":"2025101710550292000_61.4.385.24","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s10585-021-10087-x","article-title":"Breast cancer disparities in outcomes; unmasking biological determinants associated with racial and genetic diversity","volume":"39","author":"Martini","year":"2022","journal-title":"Clin Exp Metastasis"},{"key":"2025101710550292000_61.4.385.25","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-20-1319"},{"key":"2025101710550292000_61.4.385.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-019-0459-4"},{"key":"2025101710550292000_61.4.385.27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.TM118.000372"},{"key":"2025101710550292000_61.4.385.28","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.37.1476"},{"key":"2025101710550292000_61.4.385.29","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-0310"},{"key":"2025101710550292000_61.4.385.30","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s41571-021-00565-2","article-title":"Treatment landscape of triple-negative breast cancer\u2014expanded options, evolving needs","volume":"19","author":"Bianchini","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"2025101710550292000_61.4.385.31","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30891-4"},{"key":"2025101710550292000_61.4.385.32","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1093\/jnci\/djab151","article-title":"Association of genetic testing results with mortality among women with breast cancer or ovarian cancer","volume":"114","author":"Kurian","year":"2022","journal-title":"J Natl Cancer Inst"},{"key":"2025101710550292000_61.4.385.33","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-76385-8","article-title":"Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes","volume":"10","author":"De Talhouet","year":"2020","journal-title":"Sci Rep"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2023-109671","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T17:55:11Z","timestamp":1760723711000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2023-109671"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,16]]},"references-count":33,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,3,21]]},"published-print":{"date-parts":[[2024,4]]}},"alternative-id":["10.1136\/jmg-2023-109671"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2023-109671","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,16]]}}}