Curating the Clinical Genome 2024 ePoster Gallery-A Quantitative Bayesian Informed Approach to TP53-Specific Germline Variant Curation Revised Variant Curation Guidelines Improve Analysis of Germline TP53 Variants for Li-Fraumeni Syndrome

A Quantitative Bayesian Informed Approach to TP53-Specific Germline Variant Curation Revised Variant Curation Guidelines Improve Analysis of Germline TP53 Variants for Li-Fraumeni Syndrome

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The document discusses how revised variant curation guidelines for germline TP53 variants improve the analysis of these variants for Li-Fraumeni syndrome. The Clinical Genome Resource (ClinGen) TP53 Variant Curation Expert Panel (VCEP) developed updated guidelines incorporating a quantitative Bayesian approach for final variant classification. These guidelines aim to reduce variants of uncertain significance (VUS) and classification discrepancies. The revised guidelines were piloted on 43 variants, resulting in improved classification accuracy. The updated rules utilize a Bayesian-based points summary approach for combination criteria. Key modifications include the exclusion and inclusion of specific guidelines, utilizing a points system for variant classification, and achieving clinically meaningful interpretations for most variants. The document highlights the importance of accurate and consistent variant classification to guide cancer surveillance recommendations and reduce cancer-related mortality for individuals with germline TP53 variants. The results suggest that the updated guidelines lead to stronger variant classifications, fewer VUS, and potentially improved clinical care for those with TP53 variants. The full guidelines are publicly available on the ClinGen Criteria Specification Registry for reference.

Keywords

germline TP53 variants

Li-Fraumeni syndrome

Clinical Genome Resource

ClinGen

variant classification

Bayesian approach

variants of uncertain significance

cancer surveillance recommendations

revised guidelines

ClinGen Criteria Specification Registry

Megan Frone (megan.frone@nih.gov)