The ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology, and variant interpretation. This VCEP made specifications for the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines for the ataxia telangiectasia mutated (ATM) gene according to the ClinGen protocol. These gene-specific rules for ATM were modified from the ACMG/AMP guidelines and were tested against 33 ATM variants of various types and classifications in a pilot curation phase. The pilot revealed a majority agreement between the HBOP VCEP classifications and the ClinVar-deposited classifications. Six pilot variants had conflicting interpretations in ClinVar, and re-evaluation with the VCEP’s ATM-specific rules resulted in four that were classified as benign, one as likely pathogenic, and one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretations in the public domain. Overall, 28 of the 33 pilot variants were not VUS, leading to an 85% classification rate. The ClinGen-approved, modified rules demonstrated value for improved interpretation of variants in ATM.

中文翻译：

---

用于种系 ATM 序列变异分析的 ACMG/AMP 变异管理指南规范


ClinGen 遗传性乳腺癌、卵巢癌和胰腺癌 （HBOP） 变异管理专家组 （VCEP） 由临床遗传学、分子生物学和变异解释领域的国际公认专家组成。该 VCEP 根据 ClinGen 方案为美国医学遗传学学会和分子病理学协会 （ACMG/AMP） 指南制定了共济失调毛细血管扩张症突变 （ATM） 基因的规范。这些 ATM 基因特异性规则是从 ACMG/AMP 指南修改而来的，并在试点管理阶段针对 33 种不同类型和分类的 ATM 变体进行了测试。试点显示 HBOP VCEP 分类和 ClinVar 沉积分类之间的多数一致性。6 个试点变体在 ClinVar 中存在相互冲突的解释，使用 VCEP 的 ATM 特定规则进行重新评估，导致 4 个被 VCEP 归类为良性，1 个被归类为可能致病性，1 个被归类为意义不明的变体 （VUS），从而提高了公有领域解释的确定性。总体而言，33 个试点变体中有 28 个不是 VUS，分类率为 85%。ClinGen 批准的修改规则证明了改进 ATM 中变体解释的价值。