致病性 APC 体质变异是家族性腺瘤性息肉病（最常见的遗传性胃肠道息肉病综合征）的基础。为了改进变异分类并解决不确定意义变异 (VUS) 的解释挑战，ClinGen-InSiGHT 遗传性结直肠癌/息肉病变异治疗专家组 (VCEP) 根据美国的标准制定了 APC 特异性变异分类标准。医学遗传学和基因组学学院以及分子病理学协会 (ACMG/AMP)。开发了一种使用 APC 特定标准的简化算法，并应用于评估 ClinVar 和国际胃肠遗传性肿瘤协会 (InSiGHT) 国际参考 APC Leiden 开放变异数据库 (LOVD) 变异数据库中的所有 APC 变异，该数据库总共包含 10,228 个变异独特的 APC 变种。在初始分类为（可能）良性或（可能）致病的 ClinVar 和 LOVD 变体中，94% 和 96% 分别保留在其原始类别中。相比之下，41% 的 ClinVar 和 61% 的 LOVD VUS 被重新分类为有临床意义的类别，其中绝大多数（可能）为良性。 VUS 总数减少了 37%。尽管存在致病性证据，但在 37 个有希望的 APC 变体中，有 24 个 (65%) 仍保留 VUS，数据挖掘驱动的检查允许将它们重新分类为（可能）致病性。这些结果表明，应用 APC 特定标准大大减少了 ClinVar 和 LOVD 中 VUS 的数量。该研究还证明了在大型数据集中进行变异分类的系统方法的可行性，该方法可以作为其他基因或疾病特异性变异解释举措的通用模型。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。该 APC 变体子集已获得 VCEP 批准，并通过 ClinVar 和 LOVD 公开供广泛临床使用。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.