Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history

Abstract

Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer disorder associated with pathogenic germline variants in TP53, with a high penetrance over an individual's lifetime. The actual population prevalence of pathogenic germline TP53 mutations is still unclear. The aim of this study was to estimate the prevalence of potentially pathogenic TP53 exonic variants in three data sources, totaling 63,983 unrelated individuals from three sequencing databases. Potential pathogenicity was defined using an original algorithm combining bioinformatic prediction tools, clinical significance evidences, and functional data. We identified 34 different potentially pathogenic TP53 variants in 131/63,983 individuals (0.2%). Twenty-eight (82%) of these variants fell within the DNA-binding domain of TP53, with an enrichment for specific variants which were not previously identified as LFS mutation hotspots, such as the p.R290H and p.N235S variants. Our findings reveal that the population prevalence of potentially pathogenic TP53 variants may be up to 10 times higher than previously estimated from family-based studies. These results point to the need for further studies aimed at evaluating cancer penetrance modifiers as well as the risk associated between cancer and rare TP53 variants.

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