p53 major hotspot variants are associated with poorer prognostic features in hereditary cancer patients.

TP53 pathogenic germline variation is associated with the multi-cancer predisposition Li-Fraumeni syndrome (LFS). Next-generation sequencing and multigene panel testing are highlighting variability in the clinical presentation of patients with TP53 positive results. We aimed to investigate if the p53 variants considered as major hotspots at both germline and somatic levels (p.Arg175His, p.Gly245Asp, p.Gly245Ser, p.Arg248Gln, p.Arg248Trp, p.Arg273Cys, p.Arg273His, and p.Arg282Trp) were associated with poorer prognostic features compared to other pathogenic missense variants in the DNA-binding domain. To do so, we assessed clinical features from 1025 carriers of germline TP53 pathogenic variants (749 probands and 276 relatives) from three independent datasets (IARC TP53 Database, Ambry Single Gene Testing, and Ambry Multigene Panel Testing). We observed that, compared to carriers of non-hotspot germline variants, individuals that carried a hotspot germline variant were more likely to present with a Classic LFS phenotype, earlier age of first breast cancer onset, and shorter time to diagnosis to any cancer. Further studies with larger datasets addressing differences in cancer phenotypes by genotype are thus needed to replicate our findings and consider variant effect and position, towards future personalized clinical management of pathogenic variant carriers.