Clinical classification and molecular interpretation of germline pathogenic TP53 variations detected by multigene panel testing in patients with possible cancer predisposition.

Advances in high-throughput sequencing have increased the detection of TP53 variations, many of which occur at low allelic fractions. Such variants may arise due to clonal hematopoiesis (CHIP) or constitutional mosaicism, complicating their clinical classification and management. Since guidelines recommend Li-Fraumeni syndrome (LFS)-like management for individuals carrying TP53 variations, accurately determining the origin of low variant allelic fraction (VAF) variants is essential for risk assessment and clinical decision-making. This study evaluates TP53 VAF in patients with suspected hereditary cancer predisposition, tested via multigene panels and emphasizes the importance of conducting a detailed investigation before making clinical decisions in patients with low-VAF. In retrospectively analyzed 1,520 cases, we identified 17 actionable TP53 variations in 16 cases (1%). All cases were female (mean cancer onset age of 45.9 years) and classified as attenuated LFS. Eleven of the variants had an allelic fraction of ≤ 20%. Patients over 60 years showed significantly lower VAF than those under 40 (p = 0.03). The TP53 variant was detected in only one ancillary sample, and her tumor sample was monoallelic, confirming the germline origin. For an accurate classification and successful management of cases with TP53 variations, defining the origin of variants, especially for low VAF, is imperative.