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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0236907 |
| _version_ | 1819292500714586112 |
|---|---|
| author | Hideki Tokunaga Keita Iida Atsushi Hozawa Soichi Ogishima Yoh Watanabe Shogo Shigeta Muneaki Shimada Yumi Yamaguchi-Kabata Shu Tadaka Fumiki Katsuoka Shin Ito Kazuki Kumada Yohei Hamanaka Nobuo Fuse Kengo Kinoshita Masayuki Yamamoto Nobuo Yaegashi Jun Yasuda |
| author_facet | Hideki Tokunaga Keita Iida Atsushi Hozawa Soichi Ogishima Yoh Watanabe Shogo Shigeta Muneaki Shimada Yumi Yamaguchi-Kabata Shu Tadaka Fumiki Katsuoka Shin Ito Kazuki Kumada Yohei Hamanaka Nobuo Fuse Kengo Kinoshita Masayuki Yamamoto Nobuo Yaegashi Jun Yasuda |
| author_sort | Hideki Tokunaga |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-24T03:55:31Z |
| format | Article |
| id | doaj.art-014ef2600e824554a7a63914bbab854f |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-24T03:55:31Z |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-014ef2600e824554a7a63914bbab854f2022-12-21T17:16:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01161e023690710.1371/journal.pone.0236907Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2).Hideki TokunagaKeita IidaAtsushi HozawaSoichi OgishimaYoh WatanabeShogo ShigetaMuneaki ShimadaYumi Yamaguchi-KabataShu TadakaFumiki KatsuokaShin ItoKazuki KumadaYohei HamanakaNobuo FuseKengo KinoshitaMasayuki YamamotoNobuo YaegashiJun YasudaIdentification 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.https://doi.org/10.1371/journal.pone.0236907 |
| spellingShingle | Hideki Tokunaga Keita Iida Atsushi Hozawa Soichi Ogishima Yoh Watanabe Shogo Shigeta Muneaki Shimada Yumi Yamaguchi-Kabata Shu Tadaka Fumiki Katsuoka Shin Ito Kazuki Kumada Yohei Hamanaka Nobuo Fuse Kengo Kinoshita Masayuki Yamamoto Nobuo Yaegashi Jun Yasuda Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2). PLoS ONE |
| 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 |
| url | https://doi.org/10.1371/journal.pone.0236907 |
| work_keys_str_mv | AT hidekitokunaga novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT keitaiida novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT atsushihozawa novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT soichiogishima novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT yohwatanabe novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT shogoshigeta novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT muneakishimada novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT yumiyamaguchikabata novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT shutadaka novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT fumikikatsuoka novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT shinito novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT kazukikumada novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT yoheihamanaka novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT nobuofuse novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT kengokinoshita novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT masayukiyamamoto novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT nobuoyaegashi novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 AT junyasuda novelcandidatesofpathogenicvariantsofthebrca1andbrca2genesfromadatasetof3552japanesewholegenomes35kjpnv2 |