Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) based on the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP). A streamlined algorithm using the APC-specific criteria was developed and applied to assess all APC variants in ClinVar and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) international reference APC Leiden Open Variation Database (LOVD) variant database, which included a total of 10,228 unique APC variants. Among the ClinVar and LOVD variants with an initial classification of (likely) benign or (likely) pathogenic, 94% and 96% remained in their original categories, respectively. In contrast, 41% ClinVar and 61% LOVD VUSs were reclassified into clinically meaningful classes, the vast majority as (likely) benign. The total number of VUSs was reduced by 37%. In 24 out of 37 (65%) promising APC variants that remained VUS despite evidence for pathogenicity, a data-mining-driven work-up allowed their reclassification as (likely) pathogenic. These results demonstrated that the application of APC-specific criteria substantially reduced the number of VUSs in ClinVar and LOVD. The study also demonstrated the feasibility of a systematic approach to variant classification in large datasets, which might serve as a generalizable model for other gene- or disease-specific variant interpretation initiatives. It also allowed for the prioritization of VUSs that will benefit from in-depth evidence collection. This subset of APC variants was approved by the VCEP and made publicly available through ClinVar and LOVD for widespread clinical use.

中文翻译：

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ClinGen-InSiGHT APC 特异性 ACMG/AMP 变异分类标准的大规模应用导致 VUS 的大幅降低


致病性体质 APC 变异是家族性腺瘤性息肉病的基础，是最常见的遗传性胃肠道息肉病综合征。为了改进变异分类并解决意义不明变异 （VUS） 的解释挑战，ClinGen-InSiGHT 遗传性结直肠癌/息肉病变异管理专家小组 （VCEP） 根据美国医学遗传学和基因组学学院和分子病理学协会 （ACMG/AMP） 的标准制定了 APC 特异性变异分类标准。开发了一种使用 APC 特定标准的简化算法，并将其应用于评估 ClinVar 和国际胃肠道遗传性肿瘤学会 （InSiGHT） 国际参考 APC 莱顿开放变异数据库 （LOVD） 变异数据库中的所有 APC 变异，该数据库共包括 10,228 个独特的 APC 变异。在初始分类为（可能）良性或（可能）致病性的 ClinVar 和 LOVD 变体中，分别有 94% 和 96% 保留在其原始类别中。相比之下，41% 的 ClinVar 和 61% 的 LOVD VUS 被重新分类为具有临床意义的类别，其中绝大多数为（可能）良性。VUS 总数减少了 37%。在 37 个有希望的 APC 变体中，有 24 个 （65%） 尽管有致病性证据，但仍保持 VUS，数据挖掘驱动的检查允许它们被重新分类为（可能）致病。这些结果表明，APC 特异性标准的应用大大减少了 ClinVar 和 LOVD 中 VUS 的数量。该研究还证明了在大型数据集中采用系统方法进行变异分类的可行性，该方法可作为其他基因或疾病特异性变异解释计划的通用模型。 它还允许对 VUS 进行优先排序，这些 VUS 将受益于深入的证据收集。APC 变体的这一子集已获得 VCEP 的批准，并通过 ClinVar 和 LOVD 公开提供，用于广泛的临床应用。