Low-penetrance TP53 variants are mainly hypomorphic: an underestimated issue with high clinical significance.

Missense mutations that inactivate p53 are common in cancer. LiFraumeni syndrome, which is linked to early-onset cancer, is caused by germline mutations in TP53. Full-penetrant, inactive variants have garnered great attention, whereas low-penetrant variants are less well understood despite their clinical importance. This study systematically leveraged the 2025 UMD_TP53 database to identify missense variants that exhibit a statistically skewed germline-versus-somatic ratio (GVSr). Unlike classic hotspots that are equally prevalent in somatic and germline settings, these variants were disproportionately found in the germline, suggesting they act as low-penetrance variants with insufficient potency to drive tumorigenesis as single somatic events. To define the biological basis of LPVs, we integrated functional data from multiplexed assays of variant effects, tumor cell transcriptome analyses and computational predictive tools. This characterization revealed that these high-GVSr p53 variants consistently retain intermediate transcriptional activity and growth-suppressive function, classifying them distinctively as hypomorphic alleles rather than loss-of-function mutants. Our findings highlight the complexity of TP53 variant effects and underscore the importance of refined functional classification. Recognizing and accurately characterizing hypomorphic variants associated with low-penetrance cancer risk are essential for precision oncology, as they will improve genetic counseling, risk stratification, and tailored surveillance strategies for individuals with TP53 mutations.