{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T03:14:56Z","timestamp":1783480496975,"version":"3.55.0"},"reference-count":50,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T00:00:00Z","timestamp":1663804800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"Dutch Cancer Society","doi-asserted-by":"crossref","award":["UL2014-7473"],"award-info":[{"award-number":["UL2014-7473"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2022,7,19]]},"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS<jats:sub>313<\/jats:sub>) relative to standard gene testing in non-<jats:italic>BRCA1\/2<\/jats:italic> Dutch BC families.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We included 3918 BC cases from 3492 Dutch non-<jats:italic>BRCA1\/2<\/jats:italic> BC families and 3474 Dutch population controls. The association of the standardised PRS<jats:sub>313<\/jats:sub> with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS<jats:sub>313<\/jats:sub>. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in <jats:italic>ATM<\/jats:italic>, <jats:italic>CHEK2<\/jats:italic> and <jats:italic>PALB2<\/jats:italic> was known.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The family history-adjusted PRS<jats:sub>313<\/jats:sub> was significantly associated with BC (per SD OR=1.97, 95%\u2009CI 1.84 to 2.11). Including the PRS<jats:sub>313<\/jats:sub> in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS<jats:sub>313<\/jats:sub> had the largest impact for <jats:italic>CHEK2<\/jats:italic> and <jats:italic>ATM<\/jats:italic>.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our results support the application of the PRS<jats:sub>313<\/jats:sub> in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2022-108502","type":"journal-article","created":{"date-parts":[[2022,9,22]],"date-time":"2022-09-22T13:25:34Z","timestamp":1663853134000},"page":"327-336","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":35,"title":["Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases"],"prefix":"10.1136","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2990-7154","authenticated-orcid":false,"given":"Inge M M","family":"Lakeman","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar D M","family":"Rodr\u00edguez-Girondo","sequence":"additional","affiliation":[{"name":"Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0677-0252","authenticated-orcid":false,"given":"Andrew","family":"Lee","sequence":"additional","affiliation":[{"name":"Public Health and Primary Care, University of Cambridge Centre for Cancer Genetic Epidemiology, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandi","family":"Celosse","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merel E","family":"Braspenning","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaartje","family":"van Engelen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irma","family":"van de Beek","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam UMC Locatie VUmc, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemiek H","family":"van der Hout","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Medical Centre Groningen, Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Encarna B","family":"G\u00f3mez Garc\u00eda","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3805-877X","authenticated-orcid":false,"given":"Arjen R","family":"Mensenkamp","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margreet G E M","family":"Ausems","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maartje J","family":"Hooning","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muriel A","family":"Adank","sequence":"additional","affiliation":[{"name":"Family Cancer Clinic, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antoinette","family":"Hollestelle","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjanka K","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"Division of Psychosocial Research and Epidemiology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christi J","family":"van Asperen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8023-2009","authenticated-orcid":false,"given":"Peter","family":"Devilee","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands"},{"name":"Department of Pathology, Leiden University Medical Center, Leiden, The 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A polygenic risk score for breast cancer in U. S. Latinas and Latin-American women. 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