A substantial proportion of pathogenic variants associated with an increased risk of hereditary cancer are sequence variants affecting RNA splicing. The classification of these variants can be complex when both non-functional and functional transcripts are produced from the variant allele. We present four BRCA2 splice site variants with complex variant interpretations (BRCA2 c.68-3T>G, c.68-2A>G, c.425G>T, c.8331+2T>C). Evidence supporting a pathogenic classification is available for each variant, including in silico models, absence in population databases, and published functional data. However, comprehensive RNA analysis showed that some functional transcript may be produced by each variant. BRCA2 c.68-3T>G results in a partial splice defect. For BRCA2 c.68-2A>G and c.425G>T, aberrant splicing was shown to produce a potentially functional, in-frame transcript. BRCA2 c.8331+2T>C may utilize a functional GC donor in place of the wild-type GT donor. The severity of cancer history for carriers of these variants was also assessed using a history weighting algorithm and was not consistent with pathogenic controls (carriers of known pathogenic variants in BRCA2). Due to the conflicting evidence, our laboratory classifies these BRCA2 variants as variants of uncertain significance. This highlights the importance of evaluating new and existing evidence to ensure accurate variant classification and appropriate patient care.

与遗传性癌症风险增加相关的大部分致病变异是影响 RNA 剪接的序列变异。当从变体等位基因产生非功能性和功能性转录物时，这些变体的分类可能很复杂。我们提出了四种具有复杂变异解释的BRCA2剪接位点变异（ BRCA2 c.68-3T>G、c.68-2A>G、c.425G>T、c.8331+2T>C）。每个变体都有支持致病分类的证据，包括计算机模型、人口数据库中的缺失以及已发布的功能数据。然而，综合 RNA 分析表明，每个变体可能会产生一些功能性转录本。BRCA2 c.68-3T>G 导致部分剪接缺陷。为了BRCA2 c.68-2A>G 和 c.425G>T，异常剪接显示出产生潜在功能性的框内转录本。BRCA2 c.8331+2T>C 可以利用功能性 GC 供体代替野生型 GT 供体。还使用历史加权算法评估了这些变异携带者的癌症病史严重程度，并且与致病对照（BRCA2中已知致病变异的携带者）不一致。由于存在相互矛盾的证据，我们的实验室将这些BRCA2变体分类为意义不确定的变体。这突出了评估新证据和现有证据以确保准确的变异分类和适当的患者护理的重要性。