We identified a rare missense germline mutation in BARD1 (c.403G>A or p.Asp135Asn) as pathogenic using integrated genomics and transcriptomics profiling of germline and tumor samples from an early-onset triple-negative breast cancer patient who later was administrated with a PARP inhibitor for 2 months. We demonstrated in cell and mouse models that, compared to the wild-type, (1) c.403G>A mutant cell lines were more sensitive to irradiation, a DNA damage agent, and a PARP inhibitor; (2) c.403G>A mutation inhibited interaction between BARD1 and RAD51 (but not BRCA1); and (3) c.403G>A mutant mice were hypersensitive to ionizing radiation. Our study shed lights on the clinical interpretation of rare germline mutations of BARD1.

中文翻译：

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罕见错义 BARD1 c.403G 的功能后果>在三阴性乳腺癌患者中鉴定的种系突变

我们使用来自早发性三阴性乳腺癌患者的生殖系和肿瘤样本的综合基因组学和转录组学分析确定了 BARD1（c.403G>A 或 p.Asp135Asn）中罕见的错义种系突变为致病性，该患者后来接受了PARP抑制剂2个月。我们在细胞和小鼠模型中证明，与野生型相比，(1) c.403G>A 突变细胞系对辐射、DNA 损伤剂和 PARP 抑制剂更敏感；(2) c.403G>A 突变抑制 BARD1 和 RAD51 之间的相互作用（但不抑制 BRCA1）；(3) c.403G>A 突变小鼠对电离辐射过敏。我们的研究阐明了 BARD1 罕见种系突变的临床解释。