BACKGROUND Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations. We investigated BRCA1/2 prevalence and impact in the electronic health record (EHR)-linked BioMe Biobank in New York City. METHODS Exome sequence data from 30,223 adult BioMe participants were evaluated for pathogenic variants in BRCA1/2. Prevalence estimates were made in population groups defined by genetic ancestry and self-report. EHR data were used to evaluate clinical characteristics of variant-positive individuals. RESULTS There were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. The highest prevalence was in individuals with Ashkenazi Jewish (AJ; 1 in 49), Filipino and other Southeast Asian (1 in 81), and non-AJ European (1 in 103) ancestry. Among 218 variant-positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants (BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 8 had a Puerto Rican founder variant (BRCA2 c.3922G>T), and 24 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar or that had uncertain or conflicting evidence for pathogenicity (uncertain/conflicting). Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion of African genetic ancestry and the likelihood of harboring an uncertain/conflicting variant. Approximately 28% of variant-positive individuals had a personal history, and 45% had a personal or family history of BRCA1/2-associated cancers. Approximately 27% of variant-positive individuals had prior clinical genetic testing for BRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (39%) than those with other pathogenic variants (20%). CONCLUSIONS These findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.

中文翻译：

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外显子组测序揭示了基于不同人群的生物库中 BRCA1 和 BRCA2 创始人变异的高流行率。

背景 BRCA1 和 BRCA2 (BRCA1/2) 的致病性变异会导致乳腺癌、卵巢癌和其他癌症的风险增加，但一般人群中大多数变异阳性个体并没有意识到其风险，而且对于非乳腺癌中的患病率知之甚少。欧洲人口。我们调查了纽约市电子健康记录 (EHR) 关联的 BioMe 生物库中的 BRCA1/2 患病率和影响。方法 对 30,223 名成年 BioMe 参与者的外显子组序列数据进行了 BRCA1/2 致病性变异的评估。患病率估计是在由遗传血统和自我报告定义的人群中进行的。EHR 数据用于评估变异阳性个体的临床特征。结果 有 218 名个体（0.7%）携带预期的致病性变异，总体患病率为 1:139。患病率最高的是德系犹太人（AJ；49 人中有 1 人）、菲律宾人和其他东南亚人（81 人中有 1 人） ），以及非 AJ 欧洲血统（103 人中有 1 人）。在 218 名变异阳性个体中，112 人 (51.4%) 携带已知的创始人变异：80 人具有 AJ 创始人变异（BRCA1 c.5266dupC 和 c.68_69delAG，以及 BRCA2 c.5946delT），8 人具有波多黎各创始人变异（BRCA2 c.5946delT）。 3922G>T），24 人拥有其他 19 个创始人变体之一。非欧洲人群更有可能携带未在 ClinVar 中分类的 BRCA1/2 变异，或者致病性证据不确定或相互矛盾（不确定/冲突）。在混合血统人群中，例如具有非洲、欧洲和美洲遗传血统的西班牙裔/拉丁美洲人，非洲遗传血统的比例与携带不确定/冲突变异的可能性之间存在很强的相关性。大约 28% 的变异阳性个体有个人病史，45% 有 BRCA1/2 相关癌症的个人或家族史。大约 27% 的变异阳性个体之前接受过 BRCA1/2 临床基因检测。然而，携带 AJ 创始人变异的个体进行临床测试的可能性 (39%) 是携带其他致病变异 (20%) 的个体的两倍。结论 这些发现加深了我们对不同人群中 BRCA1/2 变异和相关癌症风险的了解，表明对非欧洲人群中潜在癌症相关变异的了解存在差距，并表明对不同患者群体进行基因组筛查可能是一种有效的工具识别高危人群。