Language
English
Publication Date
10-22-2025
Journal
Genome Medicine
DOI
10.1186/s13073-025-01536-3
PMID
41126324
PMCID
PMC12548217
PubMedCentral® Posted Date
10-22-2025
PubMedCentral® Full Text Version
Post-print
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. Whenever feasible, the VCEP followed a data-driven approach using likelihood ratio-based quantitative analyses to guide code application and determine strength modifications, while also factoring in expert judgment. Proposed modifications were first discussed in working group meetings and then subjected to comprehensive review during monthly general VCEP meetings to reach consensus.
Results: The performance of new specifications was compared to that of the old specifications for 43 pilot variants, and led to both decreased VUS and increased certainty, with clinically meaningful classifications for 93% of variants.
Conclusions: The updated TP53 specfications are expected to reduce VUS rates, increase inter-laboratory concordance, and improve medical management for individuals with germline TP53 variants.
Keywords
Li-Fraumeni Syndrome, Humans, Germ-Line Mutation, Tumor Suppressor Protein p53, Bayes Theorem, Genetic Predisposition to Disease, TP53, Li-Fraumeni syndrome, ACMG guidelines, ClinGen Variant Curation Expert Panel (VCEP)
Published Open-Access
yes
Recommended Citation
Fortuno, Cristina; Frone, Megan N; Mester, Jessica; et al., "A Quantitative, Bayesian-Informed Approach to Gene-Specific Variant Classification: Updated Expert Panel Recommendations Improve Classification of TP53 Germline Variants for Li-Fraumeni Syndrome" (2025). Faculty and Staff Publications. 5147.
https://digitalcommons.library.tmc.edu/baylor_docs/5147
Included in
Genetic Phenomena Commons, Genetic Processes Commons, Genetic Structures Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Medical Specialties Commons
Comments
The most current version is available at the ClinGen Criteria Specifications Registry (CSpec):https://cspec.genome.network/cspec/ui/svi/svi/GN009.