Single germline nucleotide pathogenic variants have been identified in 12 breast cancer predisposition genes, but structural deletions in these genes remain poorly characterized. We conducted in-depth whole genome sequencing (WGS) in genomic DNA samples obtained from 1340 invasive breast cancer cases and 675 controls of African ancestry. We identified 25 deletions in the intragenic regions of ten established breast cancer predisposition genes based on a consensus call from six state-of-the-art SV callers. Overall, no significant case–control difference was found in the frequency of these deletions. However, 1.0% of cases and 0.3% of controls carried any of the eight putative protein-truncating rare deletions located in BRCA1, BRCA2, CDH1, TP53, NF1, RAD51D, RAD51C and CHEK2, resulting in an odds ratio (OR) of 3.29 (95% CI 0.74–30.16). We also identified a low-frequency deletion in NF1 associated with breast cancer risk (OR 1.93, 95% CI 1.14–3.42). In addition, we detected 56 deletions, including six putative protein-truncating deletions, in suspected breast predisposition genes. This is the first large study to systematically search for structural deletions in breast cancer predisposition genes. Many of the deletions, particularly those resulting in protein truncations, are likely to be pathogenic. Results from this study, if confirmed in future large-scale studies, could have significant implications for genetic testing for this common cancer.

已在 12 个乳腺癌易感基因中鉴定出单种系核苷酸致病性变异，但这些基因的结构缺失仍知之甚少。我们对从 1340 名浸润性乳腺癌病例和 675 名非洲血统对照患者获得的基因组 DNA 样本进行了深入的全基因组测序 (WGS)。根据六位最先进的 SV 调用者的共识调用，我们在 10 个已确定的乳腺癌易感基因的基因内区域中鉴定出了 25 个缺失。总体而言，这些缺失的频率没有发现显着的病例对照差异。然而，1.0% 的病例和 0.3% 的对照携带位于BRCA1、BRCA2、CDH1、TP53、NF1、RAD51D、RAD51C和CHEK2的八种假定的蛋白质截短罕见缺失中的任何一种，导致比值比 (OR) 为 3.29 （95% CI 0.74–30.16）。我们还发现NF1中的低频缺失与乳腺癌风险相关（OR 1.93，95% CI 1.14-3.42）。此外，我们在可疑的乳腺易感基因中检测到 56 个缺失，其中包括 6 个推定的蛋白质截短缺失。这是第一项系统地寻找乳腺癌易感基因结构缺失的大型研究。许多缺失，特别是那些导致蛋白质截短的缺失，可能具有致病性。这项研究的结果如果在未来的大规模研究中得到证实，可能会对这种常见癌症的基因检测产生重大影响。