影响聚合酶ε和δ校对活性的种系变异会导致遗传性癌症和腺瘤性息肉病综合征，其特征是肿瘤具有高突变负荷和特定的突变谱。除了采用多种证据对基因变异进行分类之外，POLE 和 POLD1 变异分类尤其具有挑战性，因为影响相应聚合酶校对活性的非破坏性变异是与癌症相关的变异。为了满足该领域的明显需求，我们根据 ACMG/AMP（美国医学遗传学和基因组学/分子病理学协会）标准制定了基因特异性变异分类建议，用于评估非破坏性变异位于聚合酶核酸外切酶结构域的编码序列中。使用由 23 个被认为是致病性或良性的变体组成的训练集来定义 ACMG/AMP 标准的可用性和强度。除其他特征外，还考虑了群体频率、计算预测、共分离数据、表型和肿瘤数据以及功能结果。定义了位于 POLE 和 POLD1 核酸外切酶结构域中的非破坏性变体的基因特异性变体分类建议。由此产生的建议适用于文献和/或公共数据库中报告的 128 种核酸外切酶结构域变体。总共 17 种变异被分类为致病性或可能致病性，17 种变异被分类为良性或可能良性。随着有关携带者家族、肿瘤分子特征和功能测定的更多信息的出现，我们的建议在未来几年有改进的空间。为临床和科学界服务，帮助提高诊断性能，避免变异错误分类。© 2023。BioMed Central Ltd.，Springer Nature 旗下公司。

Germline variants affecting the proofreading activity of polymerases epsilon and delta cause a hereditary cancer and adenomatous polyposis syndrome characterized by tumors with a high mutational burden and a specific mutational spectrum. In addition to the implementation of multiple pieces of evidence for the classification of gene variants, POLE and POLD1 variant classification is particularly challenging given that non-disruptive variants affecting the proofreading activity of the corresponding polymerase are the ones associated with cancer. In response to an evident need in the field, we have developed gene-specific variant classification recommendations, based on the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria, for the assessment of non-disruptive variants located in the sequence coding for the exonuclease domain of the polymerases.A training set of 23 variants considered pathogenic or benign was used to define the usability and strength of the ACMG/AMP criteria. Population frequencies, computational predictions, co-segregation data, phenotypic and tumor data, and functional results, among other features, were considered.Gene-specific variant classification recommendations for non-disruptive variants located in the exonuclease domain of POLE and POLD1 were defined. The resulting recommendations were applied to 128 exonuclease domain variants reported in the literature and/or public databases. A total of 17 variants were classified as pathogenic or likely pathogenic, and 17 as benign or likely benign.Our recommendations, with room for improvement in the coming years as more information become available on carrier families, tumor molecular characteristics and functional assays, are intended to serve the clinical and scientific communities and help improve diagnostic performance, avoiding variant misclassifications.© 2023. BioMed Central Ltd., part of Springer Nature.