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

Wednesday, September 13, 2017 — Poster Session II

3:30 p.m. – 5:00 p.m.
FAES Terrace


  • KC de Andrade
  • L Mirabello
  • DR Stewart
  • E Karlins
  • R Koster
  • M Wang
  • SM Gapstur
  • MM Gaudet
  • ND Freedman
  • MT Landi
  • N Lemonnier
  • P Hainaut
  • SA Savage
  • MI Achatz


Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer disorder associated with pathogenic germline variants in TP53, with a near-complete penetrance over 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 variants in databases of individuals unselected for cancer history. We investigated TP53 variants in 63,983 unrelated individuals from three sequencing databases. Potential pathogenicity was defined using an original algorithm combining bioinformatics prediction tool, clinical significance, and functional data. We identified a total of 34 different potentially pathogenic TP53 variants in 131/63,983 individuals (0.2%). Most of these variants fell within the DNA-binding domain of TP53 (28/34; 82%), with an enrichment for specific variants not previously identified as LFS mutation hotspots, such as the p.R290H and p.N235S variants. Sequencing databases reveal that the population prevalence of potentially pathogenic TP53 variants may be up to 10 times higher than previously estimated. However, the current study is unable to address potential confounding factors such as clonal hematopoiesis. This study suggests that cancer penetrance in individuals with LFS due to pathogenic germline TP53 variants may be influenced by additional genetic or epigenetic modifiers, whereas rare TP53 variants may be associated with cancer family history patterns that do not meet clinical criteria for LFS.

Category: Genetics and Genomics