Germline pathogenic variants in TP53 are associated with Li‐Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early‐onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer‐related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53‐specific guidelines and sharing of clinical data among experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53‐specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.

中文翻译：

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种系 TP53 变体的 ACMG/AMP 变体解释指南规范

TP53的种系致病变异与 Li-Fraumeni 综合征有关，这是一种以常染色体显性遗传模式遗传的癌症易感性疾病，与恶性肿瘤的高风险相关，包括早发性乳腺癌、肉瘤、肾上腺皮质癌和脑肿瘤。对具有TP53 种系致病性变异的个体进行严格的癌症监测与降低癌症相关死亡率有关。对临床和研究实验室的种系变异进行准确和一致的分类对于确保适当的癌症监测建议非常重要。在这里，我们描述了临床基因组资源TP53变异管理专家小组 (ClinGen TP53VCEP) 专注于指定美国医学遗传学和基因组学学院以及分子病理学协会 (ACMG/AMP) 对TP53基因进行种系变异分类的指南。为 20 个 ACMG/AMP 标准制定了规范，其中 9 个被认为不适用。10 项标准的原始强度水平也根据当前证据进行了调整。与原始指南相比，使用TP53特定指南以及在专家和临床实验室之间共享临床数据导致不确定意义的变异从 28% 减少到 12%。ClinGen TP53 VCEP 建议使用这些TP53特定的 ACMG/AMP 指南作为TP53的标准策略种系变异分类。