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Li-Fraumeni syndrome (LFS) is an inherited, autosomal-dominant condition that predisposes individuals to a wide-spectrum of tumors at an early age. Approximately 70% of families with classic LFS have pathogenic variants in the tumor suppressor gene  TP53  that disrupt protein function or stability. While more than 70% of pathogenic variants in  TP53  are missense variants, the vast majority occur very infrequently, and thus their clinical significance is uncertain or conflicting. Here, we report an extremely rare  TP53  missense variant, c.799C > T (p.Arg267Trp), identified in a 2-year-old Saudi proband diagnosed with choroid plexus carcinoma (CPC) and six of his first- and second-degree relatives. CPC is frequently found in families with LFS, and this is the first detailed report of a family with this variant. Intriguingly, the proband’s father is homozygous for  TP53  c.799C > T and phenotypically normal at 39 years of age. While loss of  TP53  heterozygosity is often observed in tumors from individuals with LFS, homozygous germline  TP53  pathogenic variants are rare. Based on our analysis of this single family, we hypothesize that  TP53  c.799C > T has low or variable penetrance for LFS, with predisposition to the development of CPC. The observations from this family have furthered our understanding of the phenotypic variability that may be caused by one variant of  TP53 , even in the same family, and suggest that other factors (genetic and/or environmental) may play a role in mechanism of disease manifestation in LFS.

Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family