{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:27:10Z","timestamp":1783124830440,"version":"3.54.6"},"reference-count":33,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001698","name":"Israel Cancer Research Fund","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100001698","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Edmond J. Safra Center for Bioinformatics and Center for AI and Data Science (TAD) at Tel Aviv University","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"Edmond J. Safra Center for Bioinformatics at Tel Aviv University","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"Cancer Biology Research Center","award":["NA"],"award-info":[{"award-number":["NA"]}]},{"name":"Djerassi Oncology Center","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2026,2,4]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Penetrance of breast cancer (BC) among women who carry pathogenic variants (PVs) in\n                      <jats:italic>BRCA1<\/jats:italic>\n                      is incomplete, and the age at BC diagnosis varies considerably, even among carriers of the same PV, suggesting the involvement of genetic and non-genetic risk modifying factors. Polygenic Risk Score (PRS) models based on common sequence variants account for less than 10% of the total risk variability among\n                      <jats:italic>BRCA1<\/jats:italic>\n                      PV carriers, indicating that further genetic modifiers remain to be identified.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Here, for the first time, we applied whole-exome sequencing for this challenge, investigating a cohort of 321 Israeli women carrying the\n                      <jats:italic>BRCA1<\/jats:italic>\n                      185delAG founder PV.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In our cohort, we found that harbouring additional putatively damaging missense variants in genes involved in innate immunity was significantly associated with earlier BC onset. The HR for carrying a missense variant in genes annotated to the top-scoring immune-related gene set\n                      <jats:italic>NATURAL_KILLER_CELL_ACTIVATION<\/jats:italic>\n                      was 3.62 (95% CI 1.96 to 6.67; p=3.8\u00d710\n                      <jats:sup>-5<\/jats:sup>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings highlight a potential role for innate immune pathways as modifiers of\n                      <jats:italic>BRCA1<\/jats:italic>\n                      penetrance and support the development of more refined, personalised risk prediction models.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2025-111394","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:11Z","timestamp":1775001611000},"page":"415-420","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Damaging missense variants in innate immunity genes are associated with earlier age of breast cancer onset in\n                    <i>BRCA1<\/i>\n                    185delAG carriers"],"prefix":"10.1136","volume":"63","author":[{"given":"Sapir","family":"Shemesh","sequence":"first","affiliation":[{"name":"Department of Human Genetics and Computational Medicine, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv-Yafo, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinat","family":"Bernstein-Molho","sequence":"additional","affiliation":[{"name":"The Suzanne Levy-Gertner Oncogenetics Unit, Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel HaShomer, Israel"},{"name":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv-Yafo, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelley","family":"Shoval","sequence":"additional","affiliation":[{"name":"The Suzanne Levy-Gertner Oncogenetics Unit, Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel HaShomer, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Laitman","sequence":"additional","affiliation":[{"name":"The Suzanne Levy-Gertner Oncogenetics Unit, Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel HaShomer, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Madorsky-Feldman","sequence":"additional","affiliation":[{"name":"The Meirav High-Risk Clinic, Sheba Medical Center, Tel HaShomer, Tel Aviv District, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eitan","family":"Friedman","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv-Yafo, Israel"},{"name":"The Meirav High-Risk Clinic, Sheba Medical Center, Tel HaShomer, Tel Aviv District, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3440-1286","authenticated-orcid":false,"given":"Ran","family":"Elkon","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Computational Medicine, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv-Yafo, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"2026062508352780000_63.7.415.1","unstructured":"Petrucelli N , Daly MB , Pal T , et al . BRCA1- and brca2-associated hereditary breast and ovarian cancer. In: Adam MP , Everman DB , Mirzaa GM , et al , eds. GeneReviews. Seattle, 1993."},{"key":"2026062508352780000_63.7.415.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1415979111"},{"key":"2026062508352780000_63.7.415.3","doi-asserted-by":"publisher","DOI":"10.1007\/s10911-011-9200-x"},{"key":"2026062508352780000_63.7.415.4","doi-asserted-by":"crossref","DOI":"10.3390\/jcm12041422","article-title":"Risk-Reducing Breast and Gynecological Surgery for BRCA Mutation Carriers: A Narrative Review","volume":"12","author":"Bertozzi","year":"2023","journal-title":"J Clin Med"},{"key":"2026062508352780000_63.7.415.5","doi-asserted-by":"crossref","unstructured":"Friebel TM , Domchek SM , Rebbeck TR . Modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: systematic review and meta-analysis. J Natl Cancer Inst 2014;106. doi:10.1093\/jnci\/dju091","DOI":"10.1093\/jnci\/dju091"},{"key":"2026062508352780000_63.7.415.6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.67.0554"},{"key":"2026062508352780000_63.7.415.7","doi-asserted-by":"publisher","DOI":"10.1186\/bcr1670"},{"key":"2026062508352780000_63.7.415.8","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2020.8501","article-title":"Association of a Polygenic Risk Score With Breast Cancer Among Women Carriers of High- and Moderate-Risk Breast Cancer Genes","volume":"3","author":"Gallagher","year":"2020","journal-title":"JAMA Netw Open"},{"key":"2026062508352780000_63.7.415.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19966-5"},{"key":"2026062508352780000_63.7.415.10","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.20.01992"},{"key":"2026062508352780000_63.7.415.11","doi-asserted-by":"crossref","DOI":"10.1186\/s12885-022-09780-1","article-title":"Polygenic risk scores indicate extreme ages at onset of breast cancer in female BRCA1\/2 pathogenic variant carriers","volume":"22","author":"Borde","year":"2022","journal-title":"BMC Cancer"},{"key":"2026062508352780000_63.7.415.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-0862-x"},{"key":"2026062508352780000_63.7.415.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0609-2"},{"key":"2026062508352780000_63.7.415.14","doi-asserted-by":"crossref","DOI":"10.1038\/s42003-022-03978-6","article-title":"Copy number variants as modifiers of breast cancer risk for BRCA1\/BRCA2 pathogenic variant carriers","volume":"5","author":"Hakkaart","year":"2022","journal-title":"Commun Biol"},{"key":"2026062508352780000_63.7.415.15","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/s41431-022-01238-z","article-title":"Variable number tandem repeats (VNTRs) as modifiers of breast cancer risk in carriers of BRCA1 185delAG","volume":"31","author":"Ding","year":"2023","journal-title":"Eur J Hum Genet"},{"key":"2026062508352780000_63.7.415.16","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-14-0532"},{"key":"2026062508352780000_63.7.415.17","doi-asserted-by":"crossref","DOI":"10.1186\/s12885-019-5946-0","article-title":"Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women","volume":"19","author":"Sepahi","year":"2019","journal-title":"BMC Cancer"},{"key":"2026062508352780000_63.7.415.18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31405"},{"key":"2026062508352780000_63.7.415.19","doi-asserted-by":"crossref","first-page":"197","DOI":"10.3389\/fimmu.2014.00197","article-title":"Does the immune system naturally protect against cancer?","volume":"5","author":"Corthay","year":"2014","journal-title":"Front Immunol"},{"key":"2026062508352780000_63.7.415.20","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.12739"},{"key":"2026062508352780000_63.7.415.21","doi-asserted-by":"crossref","DOI":"10.1038\/s41392-024-01979-x","article-title":"Cold and hot tumors: from molecular mechanisms to targeted therapy","volume":"9","author":"Wu","year":"2024","journal-title":"Signal Transduct Target Ther"},{"key":"2026062508352780000_63.7.415.22","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2024-009063","article-title":"Challenges and opportunities in cancer immunotherapy: a Society for Immunotherapy of Cancer (SITC) strategic vision","volume":"12","author":"Emens","year":"2024","journal-title":"J Immunother Cancer"},{"key":"2026062508352780000_63.7.415.23","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/gim.2017.76","article-title":"Genomic diagnostics within a medically underserved population: efficacy and implications","volume":"20","author":"Strauss","year":"2018","journal-title":"Genet Med"},{"key":"2026062508352780000_63.7.415.24","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl Variant Effect Predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol"},{"key":"2026062508352780000_63.7.415.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"2026062508352780000_63.7.415.26","doi-asserted-by":"crossref","unstructured":"Cheng J , Novati G , Pan J , et al . Accurate proteome-wide missense variant effect prediction with AlphaMissense. Science 2023;381. doi:10.1126\/science.adg7492","DOI":"10.1126\/science.adg7492"},{"key":"2026062508352780000_63.7.415.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0273-5"},{"key":"2026062508352780000_63.7.415.28","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.5985"},{"key":"2026062508352780000_63.7.415.29","doi-asserted-by":"crossref","DOI":"10.1186\/s12885-018-4029-y","article-title":"Prevalence of pathogenic BRCA1\/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history","volume":"18","author":"Engel","year":"2018","journal-title":"BMC Cancer"},{"key":"2026062508352780000_63.7.415.30","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000001653"},{"key":"2026062508352780000_63.7.415.31","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5699(90)90097-S"},{"key":"2026062508352780000_63.7.415.32","doi-asserted-by":"crossref","DOI":"10.3390\/cancers17233756","article-title":"Germline Variants in the Immune Response-Related Genes: Possible Modifying Effect on Age-Dependent BRCA1 Penetrance in Breast Cancer Patient","volume":"17","author":"Kuligina","year":"2025","journal-title":"Cancers (Basel)"},{"key":"2026062508352780000_63.7.415.33","doi-asserted-by":"publisher","DOI":"10.1038\/nri3839"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2025-111394","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T15:36:20Z","timestamp":1782401780000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2025-111394"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,31]]},"references-count":33,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,6,25]]},"published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1136\/jmg-2025-111394"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2025-111394","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,31]]}}}