BackgroundPathogenic BRCA1 founder mutations (c.4035delA, c.5266dupC) contribute to 3.77% of all consecutive primary breast cancers and 9.9% of all consecutive primary ovarian cancers. Identifying germline pathogenic gene variants in patients with primary breast and ovarian cancer could significantly impact the medical management of patients. The aim of the study was to evaluate the rate of pathogenic mutations in the 26 breast and ovarian cancer susceptibility genes in patients who meet the criteria for BRCA1/2 testing and to compare the accuracy of different selection criteria for second-line testing in a founder population.MethodsFifteen female probands and 1 male proband that met National Comprehensive Cancer Network (NCCN) criteria for BRCA1/2 testing were included in the study and underwent 26-gene panel testing. Fourteen probands had breast cancer, one proband had ovarian cancer, and one proband had both breast and ovarian cancer. In a 26-gene panel, the following breast and/or ovarian cancer susceptibility genes were included: ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MEN1, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. All patients previously tested negative for BRCA1 founder mutations.ResultsIn 44% (7 out of 16) of tested probands, pathogenic mutations were identified. Six probands carried pathogenic mutations in BRCA1, and one proband carried pathogenic mutations in BRCA2. In patients, a variant of uncertain significance was found in BRCA2, RAD50, MRE11A and CDH1. The Manchester scoring system showed a high accuracy (87.5%), high sensitivity (85.7%) and high specificity (88.9%) for the prediction of pathogenic non-founder BRCA1/2 mutations.ConclusionA relatively high incidence of pathogenic non-founder BRCA1/2 mutations was observed in a founder population. The Manchester scoring system predicted the probability of non-founder pathogenic mutations with high accuracy.

中文翻译：

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在创始人群体中患有乳腺癌和卵巢癌的家庭中，BRCA1 和 BRCA2 致病性非创始人种系突变的频率很高

背景致病性 BRCA1 创始人突变（c.4035delA，c.5266dupC）导致所有连续原发性乳腺癌的 3.77% 和所有连续原发性卵巢癌的 9.9%。识别原发性乳腺癌和卵巢癌患者的种系致病基因变异可能会显着影响患者的医疗管理。该研究的目的是评估符合 BRCA1/2 检测标准的患者中 26 个乳腺癌和卵巢癌易感基因的致病突变率，并比较不同选择标准二线检测的准确性。人口。方法 15 名女性先证者和 1 名男性先证者符合国家综合癌症网络 (NCCN) 的 BRCA1/2 检测标准，并接受了 26 基因面板检测。14名先证者患有乳腺癌，1名先证者患有卵巢癌，1名先证者同时患有乳腺癌和卵巢癌。在 26 基因组中，包括以下乳腺癌和/或卵巢癌易感基因：ATM、BARD1、BLM、BRCA1、BRCA2、BRIP1、CDH1、CHEK2、EPCAM、FAM175A、MEN1、MLH1、MRE11A、MSH2、MSH6、 MUTYH、NBN、PALB2、PMS2、PTEN、RAD50、RAD51C、RAD51D、STK11、TP53 和 XRCC2。所有患者先前对 BRCA1 创始人突变进行了阴性检测。结果在 44%（16 名中的 7 名）测试的先证者中，确定了致病性突变。六名先证者携带 BRCA1 致病突变，一名先证者携带 BRCA2 致病突变。在患者中，在 BRCA2、RAD50、MRE11A 和 CDH1 中发现了一个意义不确定的变异。曼彻斯特评分系统显示出高准确度（87.5%）、高灵敏度（85. 7%) 和高特异性 (88.9%) 预测致病性非创始人 BRCA1/2 突变。结论在创始人人群中观察到致病性非创始人 BRCA1/2 突变的发生率相对较高。曼彻斯特评分系统高精度地预测了非创始人致病突变的概率。