{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T12:00:07Z","timestamp":1781265607292,"version":"3.54.1"},"reference-count":35,"publisher":"BMJ","issue":"3","funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["12754"],"award-info":[{"award-number":["12754"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003243","name":"Ministerstvo Zdravotnictv\u00ed Cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["(NU23-03-00150)"],"award-info":[{"award-number":["(NU23-03-00150)"]}],"id":[{"id":"10.13039\/501100003243","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003243","name":"Ministerstvo Zdravotnictv\u00ed Cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["(RVO-VFN 64165)"],"award-info":[{"award-number":["(RVO-VFN 64165)"]}],"id":[{"id":"10.13039\/501100003243","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018219","name":"Hospital de C\u00e2ncer de Barretos","doi-asserted-by":"publisher","award":["FAPESP (2013\/24633-2)"],"award-info":[{"award-number":["FAPESP (2013\/24633-2)"]}],"id":[{"id":"10.13039\/100018219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018219","name":"Hospital de C\u00e2ncer de Barretos","doi-asserted-by":"publisher","award":["FINEP - CT-INFRA (02\/2010)"],"award-info":[{"award-number":["FINEP - CT-INFRA (02\/2010)"]}],"id":[{"id":"10.13039\/100018219","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2025,11,23]]},"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>BRCA2<\/jats:italic>\n                      c.8351G&gt;A\u2009p.(Arg2784Gln) variant has long been classified as a variant of uncertain significance (VUS) due to conflicting evidence used in variant classification. This study aims to clarify its pathogenicity and associated risks for breast and ovarian cancer.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study was conducted by the international Evidence-based Network for the Interpretation of Germline Mutant Alleles consortium. We collected data from 29 informative families with this variant. Co-segregation likelihood ratios (LRs) were calculated using the full-likelihood method to assess pathogenicity, and cancer risks were estimated with modified segregation analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Co-segregation analysis using a grid search across scaled penetrance levels for\n                      <jats:italic>BRCA2<\/jats:italic>\n                      truncating variants yielded the strongest evidence in favour of pathogenicity, with LR maximised at approximately 20% of full penetrance (LR=11.026). Furthermore, estimated breast cancer risks were markedly higher for early onset breast cancer; women diagnosed at &lt;50 years had a HR of 4.5, compared with a HR of 1.65 for women diagnosed at \u226550 years. The estimated lifetime risks were 25% for breast cancer and 6% for ovarian cancer.\n                    <\/jats:p>\n                    <jats:p>Evidence of pathogenicity was also supported by the presence of the variant allele in two patients with Fanconi anaemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our results indicate that\n                      <jats:italic>BRCA2<\/jats:italic>\n                      c.8351G&gt;A\u2009p.(Arg2784Gln) has a disease-causing effect, with reduced penetrance, similar to other pathogenic variants in moderate risk breast cancer genes such as\n                      <jats:italic>ATM<\/jats:italic>\n                      and\n                      <jats:italic>CHEK2<\/jats:italic>\n                      . We also provide risk-adapted recommendations for clinical management. Importantly, one should be aware of a reduced penetrance as the underlying reason for conflicting results among pieces of evidence used for variant classification.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2025-111145","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T18:20:27Z","timestamp":1766082027000},"page":"157-163","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Evidence for pathogenicity of\n                    <i>BRCA2<\/i>\n                    c.8351G&gt;A p.(Arg2784Gln) and the challenges in classification of pathogenic variants with reduced penetrance"],"prefix":"10.1136","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7711-1030","authenticated-orcid":false,"given":"Setareh","family":"Moghadasi","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, 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