ReviewGenome medicine2025
A quantitative, Bayesian-informed approach to gene-specific variant classification: Updated Expert Panel recommendations improve classification of TP53 germline variants for Li-Fraumeni syndrome.
Review in Genome medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
3 citing papers in PubMed.
- A Personalized Therapeutic Approach for Liver Cancers Expressing the African-Centric P47S Variant of TP53.Molecular cancer research : MCR · 2026Article
- A scalable approach to resolving variants of uncertain significance.bioRxiv : the preprint server for biology · 2026Article
- Urgent need to recognize that Disease-Causing TP53 variants with atypical penetrance require distinct clinical recommendations.Journal of the National Cancer Institute · 2026Article
Corrections and comments
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Authors and funding
37 authors.
Funding
Abstract
backgroundGermline 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.
methodsThe 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.
resultsThe 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.
conclusionsThe updated TP53 specfications are expected to reduce VUS rates, increase inter-laboratory concordance, and improve medical management for individuals with germline TP53 variants. The most current version is available at the ClinGen Criteria Specifications Registry (CSpec): https://cspec.genome.network/cspec/ui/svi/svi/GN009 .
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