Shared inheritance reveals landscape of somatic and germline cancer risk in TP53.

Somatic TP53 variants predominate in middle-aged adults, with high VAF alleles linked to increased hematological malignancy risk, revealing a shift from germline to somatic cancer predisposition.

• Why it matters: Understanding the true origin of TP53 variants is crucial for accurate cancer risk assessment and genetic counseling, as somatic expansions can mimic inherited mutations and confound interpretation.
• What they did: Analyzing whole-exome data from 469,391 UK Biobank participants, the study combined variant allele fraction and haplotype-sharing to distinguish germline from somatic TP53 variants, focusing on pathogenicity and disease risk.
• The result: Findings show that somatic clonal expansions, especially with high VAF, are common and linked to increased blood cancer risk, offering a scalable approach to variant classification and better understanding of population-level cancer susceptibility.