{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T10:46:30Z","timestamp":1775040390209,"version":"3.50.1"},"reference-count":35,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T00:00:00Z","timestamp":1681689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22ck0106536"],"award-info":[{"award-number":["JP22ck0106536"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP22kk0305018"],"award-info":[{"award-number":["JP22kk0305018"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19H03628"],"award-info":[{"award-number":["19H03628"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K19082"],"award-info":[{"award-number":["20K19082"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K19751"],"award-info":[{"award-number":["21K19751"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Substantial numbers of variants of unknown significance (VUSs) have been identified in <jats:italic>BRCA1<\/jats:italic>\/<jats:italic>2<\/jats:italic> through genetic testing, which poses a significant clinical challenge because the contribution of these VUSs to cancer predisposition has not yet been determined. Here, we report 10 Japanese patients from seven families with breast or ovarian cancer harboring the <jats:italic>BRCA2<\/jats:italic> c.7847C&gt;T (p.Ser2616Phe) variant that was interpreted as a VUS. This variant recurs only in families from Japan and has not been reported in the global general population databases. A Japanese patient with Fanconi anemia with compound heterozygous variants c.7847C&gt;T (p.Ser2616Phe) and c.475+1G&gt;A in <jats:italic>BRCA2<\/jats:italic> was reported. In silico predictions and quantitative cosegregation analysis suggest a high probability of pathogenicity. The clinical features of the variant carriers were not specific to, but were consistent with, those of patients with hereditary breast and ovarian cancer. A validated functional assay, called the mixed\u2010all\u2010nominated\u2010in\u2010one\u2010BRCA (MANO\u2010B) method and the accurate BRCA companion diagnostic (ABCD) test, demonstrated the deleterious effects of the variant. Altogether, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG\/AMP) guidelines, this variant satisfied the \u201cPS3,\u201d \u201cPM2,\u201d \u201cPM3,\u201d and \u201cPP3\u201d criteria. We thus conclude that the <jats:italic>BRCA2<\/jats:italic> c.7847C&gt;T (p.Ser2616Phe) variant is a \u201clikely pathogenic\u201d variant that is specifically observed in the Japanese population, leading to a breast and ovarian cancer predisposition.<\/jats:p>","DOI":"10.1111\/cas.15799","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T15:00:10Z","timestamp":1681743610000},"page":"2993-3002","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The pathogenic role of the <i>BRCA2<\/i> c.<scp>7847C<\/scp>&gt;T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition"],"prefix":"10.1111","volume":"114","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4895-2759","authenticated-orcid":false,"given":"Kazuki","family":"Yamazawa","sequence":"first","affiliation":[{"name":"Department of Medical Genetics National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kokichi","family":"Sugano","sequence":"additional","affiliation":[{"name":"Department of Genetic Medicine, Sasaki Foundation Kyoundo Hospital  Tokyo Japan"},{"name":"Department of Genetic Medicine and Services National Cancer Center Hospital  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kohji","family":"Tanakaya","sequence":"additional","affiliation":[{"name":"Department of Surgery National Hospital Organization Iwakuni Clinical Center  Iwakuni Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satomi","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haruka","family":"Murakami","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moeko","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masataka","family":"Adachi","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Hospital Organization Tokyo Medical Center  Tokyo Japan"},{"name":"Department of Obstetrics and Gynecology National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Oki","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Hospital Organization Tokyo Medical Center  Tokyo Japan"},{"name":"Department of Obstetrics and Gynecology National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Makabe","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Hospital Organization Tokyo Medical Center  Tokyo Japan"},{"name":"Department of Obstetrics and Gynecology National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arisa","family":"Ueki","sequence":"additional","affiliation":[{"name":"Division of Clinical Genetic Oncology Cancer Institute Hospital, Japanese Foundation for Cancer Research  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayako","family":"Sasaoka","sequence":"additional","affiliation":[{"name":"Department of Nursing National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayako","family":"Nakashoji","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayuki","family":"Kinoshita","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuo","family":"Matsunaga","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masami","family":"Arai","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Graduate School of Medicine, Juntendo University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seigo","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Division of Breast Surgical Oncology, Department of Surgery Showa University School of Medicine  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroaki","family":"Miyata","sequence":"additional","affiliation":[{"name":"Department of Health Policy and Management Keio University School of Medicine  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masachika","family":"Ikegami","sequence":"additional","affiliation":[{"name":"Division of Cellular Signaling National Cancer Center Research Institute  Tokyo Japan"},{"name":"Department of Musculoskeletal Oncology Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4645-0181","authenticated-orcid":false,"given":"Hiroyuki","family":"Mano","sequence":"additional","affiliation":[{"name":"Division of Cellular Signaling National Cancer Center Research Institute  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8651-6136","authenticated-orcid":false,"given":"Shinji","family":"Kohsaka","sequence":"additional","affiliation":[{"name":"Division of Cellular Signaling National Cancer Center Research Institute  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Matsui","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery National Hospital Organization Tokyo Medical Center  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1089\/10906570260199357"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam7344"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2019-106368"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10689-017-0017-7"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-017-0355-1"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.3802\/jgo.2022.33.e46"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1016"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.123"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2890"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv416"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24363"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.2307\/1390807"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20880"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20896"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21627"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16141-8"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.12.013"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.210"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.3102\/1076998615606113"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2008.00944.x"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.207241"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-06581-8"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23818"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-70729-0"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-019-0690-2"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-020-00849-y"},{"issue":"10","key":"e_1_2_11_30_1","first-page":"3144","article-title":"Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population","volume":"7","author":"Sekine M","year":"2001","journal-title":"Clin Cancer Res"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.26852"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-014-0474-y"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.5985"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2081"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.02.005"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0114-z"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.15799","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,17]],"date-time":"2023-08-17T15:50:37Z","timestamp":1692287437000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.15799"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,17]]},"references-count":35,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2023,7]]}},"alternative-id":["10.1111\/cas.15799"],"URL":"https:\/\/doi.org\/10.1111\/cas.15799","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,17]]},"assertion":[{"value":"2022-10-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-04-17","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}