A quantitative, Bayesian-informed approach to gene-specific variant classification: Updated Expert Panel recommendations improve classification of TP53 germline variants for Li-Fraumeni syndrome.

ABSTRACT:

Background

Germline pathogenic variants in TP53 cause Li-Fraumeni syndrome, with significantly elevated cancer risk from infancy. Accurate classification of TP53 variants is essential to guide clinical management and surveillance, yet many variants remain classified as variants of uncertain significance (VUS). To improve classification accuracy and reduce the proportion of VUS, the ClinGen TP53 Variant Curation Expert Panel (VCEP) has updated its specifications.

Methods

The updated specifications incorporate the latest ClinGen recommendations and methodological advances, providing greater granularity for multiple evidence types, and also introduce the novel use of variant allele fraction as evidence of pathogenicity, particularly in the context of clonal hematopoiesis. Whene

SUBMITTER: Fortuno C 

PROVIDER: S-EPMC12548217 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature