Germline variants that affect the proofreading activity of polymerases epsilon (POLE) and delta (POLD1) predispose to colorectal adenomas and carcinomas, among other cancers. All cancer-associated pathogenic variants reported to date consist of non-disruptive genetic changes affecting the sequence that codifies the exonuclease domain (ED). Generally, disruptive (frameshift, stop-gain) POLE and POLD1 variants and missense variants outside the ED do not predispose to cancer. However, this statement may not be true for some, very specific variants that would indirectly affect the proofreading activity of the corresponding polymerase. We evaluated, by using multiple approaches, the possibility that POLD1 c.883G>A; p.(Val295Met), -a variant located 9 amino acids upstream the ED and present in ~0.25% of hereditary cancer patients-, affects POLD1 proofreading activity. Our findings show cumulative evidence that support no alteration of the proofreading activity and lack of association with cancer. The variant is classified as likely benign according to the ACMG/AMP guidelines.

影响聚合酶 epsilon ( POLE ) 和 delta ( POLD1 )校对活性的种系变异易患结直肠腺瘤和癌，以及其他癌症。迄今为止报道的所有与癌症相关的致病性变异都包括影响编码核酸外切酶结构域 (ED) 的序列的非破坏性遗传变化。通常， ED 之外的破坏性（移码、停止增益）POLE和POLD1变异以及错义变异不会诱发癌症。然而，对于某些会间接影响相应聚合酶的校对活性的非常具体的变体，这种说法可能不正确。我们通过使用多种方法评估了POLD1c.883G>A; p.(Val295Met)，-位于 ED 上游 9 个氨基酸并存在于约 0.25% 的遗传性癌症患者中的变体-影响 POLD1 校对活动。我们的研究结果显示累积证据支持校对活动没有改变并且与癌症缺乏关联。根据 ACMG/AMP 指南，该变体被归类为可能良性。