Background Several recent studies in the Baltic region have found extended spectrum of pathogenic variants (PV) of the BRCA1/2 genes. The aim of current study is to analyze the spectrum of the BRCA1/2 PV in population of Latvia and to compare common PV between populations of the Baltic region. Methods We present a cohort of 9543 unrelated individuals including ones with cancer and unaffected individuals from population of Latvia, who were tested for three most common BRCA1 founder PV. In second line testing, 164 founder negative high-risk individuals were tested for PV of the BRCA1/2 using next generation sequencing (NGS). Local spectrum of the BRCA1/2 PV was compared with the Baltic region by performing a literature review. Results Founder PV c.5266dupC, c.4035delA or c.181 T > G was detected in 369/9543 (3.9%) cases. Other BRCA1/2 PV were found in 44/164 (26.8%) of NGS cases. Four recurrent BRCA1 variants c.5117G > A (p.Gly1706Glu), c.4675G > A (p.Glu1559Lys), c.5503C > T (p.Arg1835*) and c.1961delA (p.Lys654fs) were detected in 18/44 (41.0%), 5/44 (11.4%), 2/44 (4.5%) and 2/44 (4.5%) cases respectively. Additionally, 11 BRCA1 PV and six BRCA2 PV were each found in single family. Conclusions By combining three studies by our group of the same cohort in Latvia, frequency of the BRCA1/2 PV for unselected breast and ovarian cancer cases is 241/5060 (4.8%) and 162/1067 (15.2%) respectively. The frequency of three “historical” founder PV is up to 87.0% (369/424). Other non-founder PV contribute to at least 13.0% (55/424) and this proportion probably will rise by increasing numbers of the BRCA1/2 sequencing. In relative numbers, c.5117G > A is currently the third most frequent PV of the BRCA1 in population of Latvia, overcoming previously known third most common founder variant c.181 T > G. In addition to three BRCA1 founder PV, a total of five recurrent BRCA1 and two recurrent BRCA2 PV have been reported in population of Latvia so far. Many of the BRCA1/2 PV reported in Latvia are shared among other populations of the Baltic region.

中文翻译：

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在波罗的海地区进行了 20 年的 BRCA1/2 研究后发现了一种新的频繁 BRCA1 复发变异 c.5117G > A (p.Gly1206Glu)：队列研究和文献综述

背景 最近在波罗的海地区进行的几项研究发现 BRCA1/2 基因的致病变异 (PV) 谱范围更广。当前研究的目的是分析拉脱维亚人群中 BRCA1/2 PV 的光谱，并比较波罗的海地区人群之间的常见 PV。方法 我们展示了 9543 名无关个体的队列，包括来自拉脱维亚人口的癌症患者和未受影响的个体，他们接受了三种最常见的 BRCA1 创始人 PV 测试。在二线测试中，使用下一代测序 (NGS) 对 164 名创始人阴性高风险个体进行了 BRCA1/2 的 PV 测试。通过文献综述，将 BRCA1/2 PV 的局部光谱与波罗的海地区进行了比较。结果 在 369/9543 (3.9%) 例中检测到方正 PV c.5266dupC、c.4035delA 或 c.181 T > G。在 44/164 (26.8%) 的 NGS 病例中发现了其他 BRCA1/2 PV。在 18 中检测到四种复发性 BRCA1 变体 c.5117G > A (p.Gly1706Glu)、c.4675G > A (p.Glu1559Lys)、c.5503C > T (p.Arg1835*) 和 c.1961delA (p.Lys654fs) /44 (41.0%)、5/44 (11.4%)、2/44 (4.5%) 和 2/44 (4.5%) 个案。此外，在单个家庭中分别发现了 11 个 BRCA1 PV 和 6 个 BRCA2 PV。结论 通过我们小组在拉脱维亚的同一队列的三项研究，未选择的乳腺癌和卵巢癌病例的 BRCA1/2 PV 频率分别为 241/5060（4.8%）和 162/1067（15.2%）。三位“历史”创始人PV的频率高达87.0%（369/424）。其他非创始人 PV 贡献至少 13.0% (55/424)，随着 BRCA1/2 测序数量的增加，这一比例可能会上升。在相对数字中，c.5117G > A 目前是拉脱维亚人群中 BRCA1 的第三个最常见的 PV，克服了先前已知的第三个最常见的创始变体 c.181 T > G。 除了三个 BRCA1 创始 PV，共有五个复发性 BRCA1 和两个复发性 BRCA2 PV迄今已在拉脱维亚人口中报道。拉脱维亚报告的许多 BRCA1/2 PV 与波罗的海地区的其他人群共享。