TP53 p.R181H is enriched in the Swedish cohort (SWEP53) and associated with a distinct breast and prostate phenotype.

Li-Fraumeni Syndrome (LFS) is a severe cancer predisposition syndrome caused by germline TP53 variants and characterized by a wide range of cancers. The TP53 variant p.R181H is enriched in the Swedish germline TP53 cohort and has distinct phenotypical characteristics. Using our nationwide Swedish germline TP53 database (SWEP53, 189 individuals, 86 families), p.R181H was identified in 22% of families (19/86), compared to just 0.6% in the National Cancer Institute (NCI) TP53 database (8/1360). Notably, p.R181H carriers had lower cancer incidence and better survival than carriers of other TP53 variants (both p < 0.0001). Female carriers primarily developed breast cancer (earliest onset 29 years), males mainly prostate cancer (earliest onset 45 years), and no cancers were observed in children. The results were confirmed using the NCI TP53 database. Tumor sequencing confirmed loss of heterozygosity. Additionally, haplotype analysis suggests that p.R181H is a potential Swedish founder variant, estimated to be ~ 550 years old. These findings indicate that, for p.R181H carriers, tailored surveillance could focus on adults by omitting children from testing and surveillance, and by targeting prevention and detection to breast cancer in females and prostate cancer in males. Validation in independent cohorts is warranted.