A pathogenic mutation in BRCA2 significantly increases the risk of breast and ovarian cancers making it imperative to examine the functional consequences of variants of uncertain clinical significance. Variants that are predicted to result in a truncated protein are unambiguously classified as pathogenic. We have previously shown how a pathogenic splice site variant known to generate a premature termination codon (PTC) in exon 9 and a nonsense mutation at exon 7, can generate functional BRCA2 by skipping exons 4-7 and restoring the reading frame. Using a well-established mouse embryonic stem cell-based assay, we functionally characterize here one splice site mutation and 11 pathogenic BRCA2 variants that are either nonsense mutation or generate PTC in different exons ranging from exons 4 to 7. Our study shows that five variants can restore the open reading frame by exon skipping and generate a functional protein. This suggests further need to exercise prudence when classifying clearly pathogenic variants.

中文翻译：

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通过外显子跳跃绕过过早终止密码子并产生功能性 BRCA2。

BRCA2 中的致病突变显着增加了乳腺癌和卵巢癌的风险，因此必须检查临床意义不确定的变异的功能后果。预测会导致截断蛋白质的变体被明确归类为致病性的。我们之前已经展示了已知在外显子 9 中产生过早终止密码子 (PTC) 和在外显子 7 处产生无义突变的致病剪接位点变异如何通过跳过外显子 4-7 并恢复阅读框来产生功能性 BRCA2。使用完善的基于小鼠胚胎干细胞的测定，我们在这里功能性地表征了一个剪接位点突变和 11 个致病性 BRCA2 变异，这些变异要么是无义突变，要么在外显子 4 到 7 的不同外显子中产生 PTC。我们的研究表明，五种变体可以通过外显子跳跃恢复开放阅读框并产生功能性蛋白质。这表明在对明确的致病变异进行分类时需要进一步谨慎。