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Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2)

Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2, is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants t...

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Autores principales: Tokunaga, Hideki, Iida, Keita, Hozawa, Atsushi, Ogishima, Soichi, Watanabe, Yoh, Shigeta, Shogo, Shimada, Muneaki, Yamaguchi-Kabata, Yumi, Tadaka, Shu, Katsuoka, Fumiki, Ito, Shin, Kumada, Kazuki, Hamanaka, Yohei, Fuse, Nobuo, Kinoshita, Kengo, Yamamoto, Masayuki, Yaegashi, Nobuo, Yasuda, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799847/
https://www.ncbi.nlm.nih.gov/pubmed/33428613
http://dx.doi.org/10.1371/journal.pone.0236907
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author Tokunaga, Hideki
Iida, Keita
Hozawa, Atsushi
Ogishima, Soichi
Watanabe, Yoh
Shigeta, Shogo
Shimada, Muneaki
Yamaguchi-Kabata, Yumi
Tadaka, Shu
Katsuoka, Fumiki
Ito, Shin
Kumada, Kazuki
Hamanaka, Yohei
Fuse, Nobuo
Kinoshita, Kengo
Yamamoto, Masayuki
Yaegashi, Nobuo
Yasuda, Jun
author_facet Tokunaga, Hideki
Iida, Keita
Hozawa, Atsushi
Ogishima, Soichi
Watanabe, Yoh
Shigeta, Shogo
Shimada, Muneaki
Yamaguchi-Kabata, Yumi
Tadaka, Shu
Katsuoka, Fumiki
Ito, Shin
Kumada, Kazuki
Hamanaka, Yohei
Fuse, Nobuo
Kinoshita, Kengo
Yamamoto, Masayuki
Yaegashi, Nobuo
Yasuda, Jun
author_sort Tokunaga, Hideki
collection PubMed
description Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2, is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants that contribute to increasing the risk of breast and ovarian cancers in a population is critical to establish personalized health care. A prospective cohort subjected to genome analysis can provide both sets of information. Computational scoring and prospective cohort studies may help to identify such likely pathogenic variants in the general population. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of a prospective cohorts with genome data in the Tohoku Medical Megabank Project (TMM) with InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAFs) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar were used for filtration criteria. Familial predispositions to cancers among the 35,000 TMM genome cohort participants were analyzed to verify the identified pathogenicity. Seven potentially pathogenic variants were newly identified. The sisters of carriers of these moderately deleterious variants and definite P and LP variants among members of the TMM prospective cohort showed a statistically significant preponderance for cancer onset, from the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potentially pathogenic variants in BRCA genes in the Japanese population. These results should help to follow up the carriers of variants of uncertain significance in the HBOC genes in the longitudinal prospective cohort study.
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spelling pubmed-77998472021-01-22 Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2) Tokunaga, Hideki Iida, Keita Hozawa, Atsushi Ogishima, Soichi Watanabe, Yoh Shigeta, Shogo Shimada, Muneaki Yamaguchi-Kabata, Yumi Tadaka, Shu Katsuoka, Fumiki Ito, Shin Kumada, Kazuki Hamanaka, Yohei Fuse, Nobuo Kinoshita, Kengo Yamamoto, Masayuki Yaegashi, Nobuo Yasuda, Jun PLoS One Research Article Identification of the population frequencies of definitely pathogenic germline variants in two major hereditary breast and ovarian cancer syndrome (HBOC) genes, BRCA1/2, is essential to estimate the number of HBOC patients. In addition, the identification of moderately penetrant HBOC gene variants that contribute to increasing the risk of breast and ovarian cancers in a population is critical to establish personalized health care. A prospective cohort subjected to genome analysis can provide both sets of information. Computational scoring and prospective cohort studies may help to identify such likely pathogenic variants in the general population. We annotated the variants in the BRCA1 and BRCA2 genes from a dataset of 3,552 whole-genome sequences obtained from members of a prospective cohorts with genome data in the Tohoku Medical Megabank Project (TMM) with InterVar software. Computational impact scores (CADD_phred and Eigen_raw) and minor allele frequencies (MAFs) of pathogenic (P) and likely pathogenic (LP) variants in ClinVar were used for filtration criteria. Familial predispositions to cancers among the 35,000 TMM genome cohort participants were analyzed to verify the identified pathogenicity. Seven potentially pathogenic variants were newly identified. The sisters of carriers of these moderately deleterious variants and definite P and LP variants among members of the TMM prospective cohort showed a statistically significant preponderance for cancer onset, from the self-reported cancer history. Filtering by computational scoring and MAF is useful to identify potentially pathogenic variants in BRCA genes in the Japanese population. These results should help to follow up the carriers of variants of uncertain significance in the HBOC genes in the longitudinal prospective cohort study. Public Library of Science 2021-01-11 /pmc/articles/PMC7799847/ /pubmed/33428613 http://dx.doi.org/10.1371/journal.pone.0236907 Text en © 2021 Tokunaga et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Tokunaga, Hideki
Iida, Keita
Hozawa, Atsushi
Ogishima, Soichi
Watanabe, Yoh
Shigeta, Shogo
Shimada, Muneaki
Yamaguchi-Kabata, Yumi
Tadaka, Shu
Katsuoka, Fumiki
Ito, Shin
Kumada, Kazuki
Hamanaka, Yohei
Fuse, Nobuo
Kinoshita, Kengo
Yamamoto, Masayuki
Yaegashi, Nobuo
Yasuda, Jun
Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2)
title Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2)
title_full Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2)
title_fullStr Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2)
title_full_unstemmed Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2)
title_short Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2)
title_sort novel candidates of pathogenic variants of the brca1 and brca2 genes from a dataset of 3,552 japanese whole genomes (3.5kjpnv2)
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799847/
https://www.ncbi.nlm.nih.gov/pubmed/33428613
http://dx.doi.org/10.1371/journal.pone.0236907
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