Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (BRCA1 and BRCA2). BRCA1-associated ring domain 1 (BARD1), nuclear partner of BRCA1, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of BARD1 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive BARD1 screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous BARD1 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating BARD1 variants with overall risk (odds ratio (OR) = 3.78; CI = 2.10–6.48; p = 1.16 × 10⁻⁵). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18; CI = 2.10–7.70; p = 5.45 × 10⁻⁵). Furthermore, deleterious BARD1 variants were enriched among triple-negative BC patients (OR = 5.40; CI = 1.77–18.15; p = 0.001) compared to other BC subtypes. Our results support the role of BARD1 as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.

中文翻译：

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BARD1致病变异与西班牙遗传性乳腺癌和卵巢癌队列中的三阴性乳腺癌相关。

仅一小部分遗传性乳腺癌和/或卵巢癌（HBOC）病例是由高渗透性乳腺癌1和2基因（BRCA1和BRCA2）中的种系变异引起的。BRCA1相关环结构域1（BARD1），核伙伴BRCA1，已被建议作为一种潜在HBOC风险基因，虽然其患病率和外显率可变，根据群体和肿瘤的类型是。我们的目的是调查临床怀疑HBOC的患者队列中BARD1截短变异体的患病率。全面的BARD1根据我们关于遗传性癌症基因检测的地区指南，对4015例无关患者进行了多基因面板分析筛选。此外，将51,202个基因组聚合数据库（gnomAD）非芬兰，非癌症的欧洲个体用作对照人群。在我们的患者队列中，我们确定了19例具有杂合性BARD1截短变异的患者（0.47％），而在gnomAD对照中观察到的频率为0.12％。我们发现截短的BARD1变异与总体风险有统计学意义的关联（优势比（OR）= 3.78； CI = 2.10–6.48；p = 1.16×10 ^-5）。这种关联在遗传性乳腺癌（HBC）组中仍然很显着（OR = 4.18; CI = 2.10–7.70; p= 5.45×10 ^-5）。此外，与其他BC亚型相比，三阴性BC患者中的有害BARD1变异体更为丰富（OR = 5.40； CI = 1.77-18.15；p = 0.001）。我们的结果支持BARD1作为中度渗透性BC易感基因的作用，并突出显示与三阴性肿瘤的更强关联。