Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants

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.