Independent somatic TP53 mutations in blood and tumor mimicking Li-Fraumeni syndrome in a 94-year-old man

Accurately determining the origin of TP53 variants detected in blood is essential as such variants may arise from the constitutional state or clonal hematopoiesis (CH). While paired tumor-blood sequencing is widely used to distinguish somatic from constitutional events, convergent acquisition of identical TP53 hotspot mutations in tumor and blood can obscure variant origin and complicate interpretation. Here we report a 94-year-old patient with the TP53 c.524 G > A (p.Arg175His) pathogenic variant identified in both peripheral blood and tumor tissue, initially raising concern for Li-Fraumeni syndrome (LFS). Given the patient’s atypical LFS clinical presentations, multi-tissue confirmatory analysis was performed. Normal bladder tissue and skin biopsy each showed trace mutant signal, and fingernail DNA was negative. These findings support independent somatic acquisition of the same TP53 hotspot mutation in hematopoietic and tumor lineages. This case highlights the importance of multi-tissue confirmatory testing to accurately determine the origin of TP53 variants in cancer patients.