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Hum Mutat. 2019 Jan;40(1):97-105. doi: 10.1002/humu.23673. Epub 2018 Nov 19.

Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis.

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Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.
International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil.
Division of Research, National Cancer Institute, Mexico City, Mexico.
Institute for Advanced Biosciences, Inserm U 1209 CNRS UMR 5309 Université Grenoble Alpes, Site Santé, Allée des Alpes, La Tronche, France.
Department of Head and Neck Surgery and Otorhinolaryngology, AC Camargo Cancer Center, São Paulo, Brazil.
Centro de Oncologia, Sírio-Libanês Hospital, São Paulo, Brazil.


Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. We previously reported higher-than-expected population prevalence estimates in sequencing databases composed of individuals unselected for cancer history. This study aimed to expand and further evaluate the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (version r2.0.2, n = 138,632). Variants were selected and classified based on our previously published algorithm and compared with alternative estimates based on three different classification databases: ClinVar, HGMD, and the UMD_TP53 database. Conservative prevalence estimates of pathogenic and likely pathogenic TP53 variants were within the range of one carrier in 3,555-5,476 individuals. Less stringent classification increased the approximate prevalence to one carrier in every 400-865 individuals, mainly due to the inclusion of the controvertible p.N235S, p.V31I, and p.R290H variants. This study shows a higher-than-expected population prevalence of pathogenic and likely pathogenic germline TP53 variants even with the most conservative estimates. However, these estimates may not necessarily reflect the prevalence of the classical LFS phenotype, which is based upon family history of cancer. Comprehensive approaches are needed to better understand the interplay of germline TP53 variant classification, prevalence estimates, cancer penetrance, and LFS-associated phenotype.


Li-Fraumeni syndrome; TP53; gnomAD; pathogenic variant; prevalence; variant classification

[Available on 2020-01-01]

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