Breast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10⁻⁹) and missense (OR 1.27, p = 3.96 × 10⁻⁷³) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.

乳腺癌 (BC) 具有显着的遗传成分，但在大多数高危 BC 家族中，遗传贡献仍未得到解决。本研究旨在调查BRCA1和BRCA2之外 BC 家族聚集的单基因原因，包括鉴定新的易感基因。在 BEACCON 研究中，共有 11,511 个非 BRCA 家族性 BC 病例和人群匹配的无癌女性对照在两个测序阶段进行了调查：多达 3892 个病例和对照中的 1303 个候选基因，随后验证了 145 个入围基因。额外的 7619 个科目。使用定制设计的测序面板对所有候选基因和 14 个先前提出的 BC 基因的编码区和外显子-内含子边界进行测序。分析系谱和病理数据以确定基因型特异性关联。ATM、PALB2和CHEK2对 BC 易感性的贡献得到证实，但未证实RAD50和NBN. 在 145 个候选基因的情况下，观察到功能丧失 (LoF) (OR 1.27, p  = 9.05 × 10 ^-9 ) 和错义 (OR 1.27, p  = 3.96 × 10 ^-73 ) 变体总体过量。主要候选者携带 LoF 变异，观察到的 OR 为 2-4，单独占病例数不超过 0.79%。本研究提出了新的基因包括NTHL1，WRN，PARP2，CTH和CDK9. BEACCON 中确定的新候选 BC 易感基因表明，高风险 BC 家族的大部分剩余遗传原因是由于基因中的致病变异非常罕见并且仅传达低至中度风险。