<title>Abstract</title>
The genetic and clinical characteristics of breast tumors with germline variants, including their association with biallelic inactivation through loss-of-heterozygosity (LOH) and second somatic mutations, remain elusive. We analyzed germline variants of 11 breast cancer susceptibility genes for 1,995 Japanese breast cancer patients, and identified 101 (5.1%) pathogenic variants, including 62 <italic>BRCA2</italic> and 15 <italic>BRCA1</italic> mutations. Genetic analysis of 64 <italic>BRCA1/2</italic>-mutated tumors including TCGA dataset tumors, revealed an association of biallelic inactivation with more extensive deletions, copy neutral LOH, gain with LOH and younger onset. Strikingly, <italic>TP53</italic> and <italic>RB1</italic> mutations were frequently observed in <italic>BRCA1-</italic> (94%) and <italic>BRCA2-</italic> (9.7%) mutated tumors with biallelic inactivation. Inactivation of <italic>TP53</italic> and <italic>RB1</italic> together with <italic>BRCA1</italic> and <italic>BRCA2</italic>, respectively, involved LOH of chromosomes 17 and 13. Notably, <italic>BRCA1/2</italic> tumors without biallelic inactivation were indistinguishable from those without germline variants. Our study highlights the heterogeneity and unique clonal selection pattern in breast cancers with germline variants.