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The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition
Substantial numbers of variants of unknown significance (VUSs) have been identified in BRCA1/2 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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323079/ https://www.ncbi.nlm.nih.gov/pubmed/37067535 http://dx.doi.org/10.1111/cas.15799 |
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author | Yamazawa, Kazuki Sugano, Kokichi Tanakaya, Kohji Inoue, Satomi Murakami, Haruka Nakashima, Moeko Adachi, Masataka Oki, Shinya Makabe, Takeshi Yamashita, Hiroshi Ueki, Arisa Sasaoka, Ayako Nakashoji, Ayako Kinoshita, Takayuki Matsunaga, Tatsuo Arai, Masami Nakamura, Seigo Miyata, Hiroaki Ikegami, Masachika Mano, Hiroyuki Kohsaka, Shinji Matsui, Akira |
author_facet | Yamazawa, Kazuki Sugano, Kokichi Tanakaya, Kohji Inoue, Satomi Murakami, Haruka Nakashima, Moeko Adachi, Masataka Oki, Shinya Makabe, Takeshi Yamashita, Hiroshi Ueki, Arisa Sasaoka, Ayako Nakashoji, Ayako Kinoshita, Takayuki Matsunaga, Tatsuo Arai, Masami Nakamura, Seigo Miyata, Hiroaki Ikegami, Masachika Mano, Hiroyuki Kohsaka, Shinji Matsui, Akira |
author_sort | Yamazawa, Kazuki |
collection | PubMed |
description | Substantial numbers of variants of unknown significance (VUSs) have been identified in BRCA1/2 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 BRCA2 c.7847C>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>T (p.Ser2616Phe) and c.475+1G>A in BRCA2 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‐all‐nominated‐in‐one‐BRCA (MANO‐B) 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 “PS3,” “PM2,” “PM3,” and “PP3” criteria. We thus conclude that the BRCA2 c.7847C>T (p.Ser2616Phe) variant is a “likely pathogenic” variant that is specifically observed in the Japanese population, leading to a breast and ovarian cancer predisposition. |
format | Online Article Text |
id | pubmed-10323079 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-103230792023-07-07 The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition Yamazawa, Kazuki Sugano, Kokichi Tanakaya, Kohji Inoue, Satomi Murakami, Haruka Nakashima, Moeko Adachi, Masataka Oki, Shinya Makabe, Takeshi Yamashita, Hiroshi Ueki, Arisa Sasaoka, Ayako Nakashoji, Ayako Kinoshita, Takayuki Matsunaga, Tatsuo Arai, Masami Nakamura, Seigo Miyata, Hiroaki Ikegami, Masachika Mano, Hiroyuki Kohsaka, Shinji Matsui, Akira Cancer Sci ORIGINAL ARTICLES Substantial numbers of variants of unknown significance (VUSs) have been identified in BRCA1/2 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 BRCA2 c.7847C>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>T (p.Ser2616Phe) and c.475+1G>A in BRCA2 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‐all‐nominated‐in‐one‐BRCA (MANO‐B) 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 “PS3,” “PM2,” “PM3,” and “PP3” criteria. We thus conclude that the BRCA2 c.7847C>T (p.Ser2616Phe) variant is a “likely pathogenic” variant that is specifically observed in the Japanese population, leading to a breast and ovarian cancer predisposition. John Wiley and Sons Inc. 2023-04-17 /pmc/articles/PMC10323079/ /pubmed/37067535 http://dx.doi.org/10.1111/cas.15799 Text en © 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | ORIGINAL ARTICLES Yamazawa, Kazuki Sugano, Kokichi Tanakaya, Kohji Inoue, Satomi Murakami, Haruka Nakashima, Moeko Adachi, Masataka Oki, Shinya Makabe, Takeshi Yamashita, Hiroshi Ueki, Arisa Sasaoka, Ayako Nakashoji, Ayako Kinoshita, Takayuki Matsunaga, Tatsuo Arai, Masami Nakamura, Seigo Miyata, Hiroaki Ikegami, Masachika Mano, Hiroyuki Kohsaka, Shinji Matsui, Akira The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition |
title | The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition |
title_full | The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition |
title_fullStr | The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition |
title_full_unstemmed | The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition |
title_short | The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition |
title_sort | pathogenic role of the brca2 c.7847c>t (p.ser2616phe) variant in breast and ovarian cancer predisposition |
topic | ORIGINAL ARTICLES |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323079/ https://www.ncbi.nlm.nih.gov/pubmed/37067535 http://dx.doi.org/10.1111/cas.15799 |
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