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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
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.
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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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