CDH1基因的生殖系致病变异与弥漫性胃癌和小叶性乳腺癌的风险增加相关。风险降低策略包括考虑预防性手术，因此准确解释CDH1基因ic的生殖系变异对于决定这些程序的医生至关重要。临床基因组资源(ClinGen) CDH1变异审核专家组(VECP)开发了CDH1变异审核规范，旨在解决未确定意义(VUS)和ClinVar冲突解释，并继续更新这些规范。CDH1变异分类规范是基于更新的遗传测试临床标准、ClinGen的新建议和持续的CDH1变异审核专家知识修正的。CDH1 VECP使用更新的规范审核了273个变异，并整合了诊断实验室提供的已发表和未发表数据。更新的CDH1特定解释指南包括自2018年最初规范以来的11个主要修正。使用完善的指南，97%(36/37)的ClinVar冲突解释变异成功分为良性、可能良性、可能致病或致病，43个VUS中的35%(15个)被分为良性或可能良性。总体而言，88%(239/273)的变异均具有非VUS分类。迄今为止，被分类为致病的变异均为无义、移码、剪接或影响翻译起始密码子的变异，仅有的可能致病的错义变异已被证明影响剪接。专家组通过开发和演变CDH1特定标准，减少了这个临床可操作基因变异的不确定和冲突解释，最终可能导致更有效的临床管理建议。©作者(或其雇主)2022年。无法进行商业再利用。请参阅权利和权限。由BMJ发表。

Germline pathogenic variants in CDH1 are associated with increased risk of diffuse gastric cancer and lobular breast cancer. Risk reduction strategies include consideration of prophylactic surgery, thereby making accurate interpretation of germline CDH1 variants critical for physicians deciding on these procedures. The Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel (VCEP) developed specifications for CDH1 variant curation with a goal to resolve variants of uncertain significance (VUS) and with ClinVar conflicting interpretations and continues to update these specifications.CDH1 variant classification specifications were modified based on updated genetic testing clinical criteria, new recommendations from ClinGen and expert knowledge from ongoing CDH1 variant curations. The CDH1 VCEP reviewed 273 variants using updated CDH1 specifications and incorporated published and unpublished data provided by diagnostic laboratories.Updated CDH1-specific interpretation guidelines include 11 major modifications since the initial specifications from 2018. Using the refined guidelines, 97% (36 of 37) of variants with ClinVar conflicting interpretations were resolved to benign, likely benign, likely pathogenic or pathogenic, and 35% (15 of 43) of VUS were resolved to benign or likely benign. Overall, 88% (239 of 273) of curated variants had non-VUS classifications. To date, variants classified as pathogenic are either nonsense, frameshift, splicing, or affecting the translation initiation codon, and the only missense variants classified as pathogenic or likely pathogenic have been shown to affect splicing.The development and evolution of CDH1-specific criteria by the expert panel resulted in decreased uncertain and conflicting interpretations of variants in this clinically actionable gene, which can ultimately lead to more effective clinical management recommendations.© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.