A quantitative, Bayesian-informed approach to gene-specific variant classification: Updated Expert Panel recommendations improve classification of TP53 germline variants for Li-Fraumeni syndrome.
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Fortuno Cristina, Frone Megan N, Mester Jessica, de la Hoya Miguel, Mai Phuong L, Pesaran Tina, Achatz Maria Isabel, Bassett Rebecca, Bustamante Carolina, Crowley Stephanie, de Andrade Kelvin Cesar, Evans D Gareth, Feng Bingjian, Fuqua Laura, Harrell Maria Isabel, Hatton Jessica N, Huether Robert, Kesserwan Chimene, Lee Kristy, MacFarland Suzanne P, Maciaszek Jamie L, Maxwell Kara, McGoldrick Kelly, Murphy Maureen, Nehoray Bita, Penkert Judith, Pinto Emilia Modolo, Plon Sharon E, Schwartz-Levine Alison, Thompson Ashley S, Wang Wenyi, Zambetti Gerard P, Zelley Kristin, James Paul A, Savage Sharon A, Kratz Christian P, Spurdle Amanda B
Аннотация
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. The most current version is available at the ClinGen Criteria Specifications Registry (CSpec): https://cspec.genome.network/cspec/ui/svi/svi/GN009 .