Journal Article

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

Yamamoto, Masayuki, Tadaka, Shu, Katsuoka, Fumiki, Yasuda, Jun, Hamanaka, Yohei, Iida, Keita, Hozawa, Atsushi, Watanabe, Yoh, Ito, Shin, Shigeta, Shogo, Yamaguchi-Kabata, Yumi, Shimada, Muneaki, Kumada, Kazuki, Ogishima, Soichi, Kinoshita, Kengo, Fuse, Nobuo, Yaegashi, Nobuo, Tokunaga, Hideki

2021

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Aging / Alleles / Biochemistry / Biology and Life Sciences / BRCA mutations / BRCA1 protein / BRCA1 Protein - genetics / BRCA1 Protein - metabolism / BRCA2 protein / BRCA2 Protein - genetics / BRCA2 Protein - metabolism / Breast cancer / Breast Neoplasms - epidemiology / Breast Neoplasms - genetics / Cancer / Clinical decision making / Cohort Studies / Computer programs / Consortia / Data analysis / Databases, Genetic / Datasets / Decision making / Deoxyribonucleic acid / DNA / Drafting software / Editing / Fallopian tube / Female / Funding / Gene Frequency - genetics / Genes / Genes, BRCA1 / Genes, BRCA2 - physiology / Genetic aspects / Genetic Predisposition to Disease - genetics / Genetic Testing - methods / Genomes / Germ-Line Mutation - genetics / Graduate schools / Graduate studies / Gynecology / Health aspects / Health risks / Hereditary Breast and Ovarian Cancer Syndrome - pathology / Heterozygote / Humans / Information science / Innovations / Japan - epidemiology / Japanese / Medicine / Medicine and Health Sciences / Middle Aged / Minority & ethnic groups / Mutation / Mutation - genetics / Obstetrics / Oncology / Oncology, Experimental / Ovarian cancer / Ovarian carcinoma / Ovarian Neoplasms - pathology / Ovariectomy / Patients / Population / Precision medicine / Prospective Studies / Research and Analysis Methods / Research facilities / Software / University graduates / Whole Genome Sequencing - methods