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Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants
medRxiv - Genetic and Genomic Medicine Pub Date : 2020-05-01 , DOI: 10.1101/2020.04.25.20078931
Cristina Fortuno , Kristy Lee , Magali Olivier , Tina Pesaran , Phuong L. Mai , Kelvin C. de Andrade , Laura D. Attardi , Stephanie Crowley , D. Gareth Evans , Bing-Jian Feng , Ann Katherine Major Foreman , Megan N. Frone , Robert Huether , Paul A. James , Kelly McGoldrick , Jessica Mester , Bryce A. Seifert , Thomas P. Slavin , Leora Witkowski , Liying Zhang , Sharon E. Plon , Amanda B. Spurdle , Sharon A. Savage

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome (LFS), an autosomal dominant cancer predisposition disorder associated with 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 has been shown to decrease mortality; therefore, accurate and consistent classification of variants across clinical and research laboratories is crucial to patient care. 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 applied to twenty ACMG/AMP criteria while nine were deemed not applicable. The original strength level for ten criteria was also adjusted due to current evidence. Use of the TP53-specific guidelines and sharing of clinical data amongst experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% in comparison 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:

种系TP53变体的ACMG / AMP变体解释指南的规范

TP53中的种系致病变异与Li-Fraumeni综合征(LFS)相关,L-Fraumeni综合征是一种常染色体显性遗传易感性疾病,与恶性肿瘤的高风险相关,包括早期发作的乳腺癌,肉瘤,肾上腺皮质癌和脑瘤。对具有TP53种系病原体变异的个体进行强力癌症监测已显示可降低死亡率。因此,在临床和研究实验室中对变体进行准确,一致的分类对于患者护理至关重要。在这里,我们描述了由临床基因组资源TP53变异治疗专家小组(ClinGen TP53 VCEP)进行的工作,该研究小组的工作重点是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)对种系变异进行分类的指南TP53基因。规范适用于20条ACMG / AMP标准,而9条被认为不适用。十个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,使用特定于TP53的指南并在专家和临床实验室之间共享临床数据可将不确定性显着性变量从28%降低到12%。ClinGen TP53 VCEP建议使用这些特定于TP53的ACMG / AMP指南作为TP53种系变异分类的标准策略。与原始指南相比,使用特定于TP53的指南并在专家和临床实验室之间共享临床数据可将不确定性显着性变量从28%降低到12%。ClinGen TP53 VCEP建议使用这些特定于TP53的ACMG / AMP指南作为TP53种系变异分类的标准策略。与原始指南相比,使用特定于TP53的指南并在专家和临床实验室之间共享临床数据可将不确定性显着性变量从28%降低到12%。ClinGen TP53 VCEP建议使用这些特定于TP53的ACMG / AMP指南作为TP53种系变异分类的标准策略。
更新日期:2020-05-01
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