A quantitative model to predict pathogenicity of missense variants in the TP53 gene

Abstract

Germline pathogenic variants in the TP53 gene cause Li-Fraumeni syndrome, a condition that predisposes individuals to a wide range of cancer types. Identification of individuals carrying a TP53 pathogenic variant is linked to clinical management decisions, such as the avoidance of radiotherapy and use of high-intensity screening programs. The aim of this study was to develop an evidence-based quantitative model that integrates independent in silico data (Align-GVGD and BayesDel) and somatic to germline ratio (SGR), to assign pathogenicity to every possible missense variant in the TP53 gene. To do this, a likelihood ratio for pathogenicity (LR) was derived from each component calibrated using..