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

Abstract

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.

Fig 1. Relationships between the variant impact scores for the BRCA genes in 3.5KJPNv2.

Panel a. Schematic diagram of filtering steps for candidate pathogenic variants in the BRCA genes. The details of the filtering process are described in the main text. MAF indicates minor allele frequency. Panel b. Distribution of candidate pathogenic variants of BRCA cDNA in 3.5KJPNv2. Schematic diagram of the BRCA1 and BRCA2 cDNA generated with Mutation Mapper on the cBioPortal. “F,” “N,” “S,” and “X” indicate frameshifts, nonsynonymous single-nucleotide variants, splicing error variants, and stopgains, respectively. The height of lollipops indicates the number of cases found in 3.5KJPNv2. Asterisks indicate variants in the computational + MAF set.

Fig 2. Preponderance of individual and family histories of cancer for the TMM CommCohort.