Performance of LFSPRO prediction in TP53 mutation status for prospectively collected probands

Genetic counseling and testing for germline mutations are essential for identifying individuals at increased risk for cancer. Pathogenic/likely pathogenic (P/LP) variants in TP53 are diagnostic of Li-Fraumeni syndrome (LFS), a highly penetrant disorder with diverse, early-onset tumors. Current clinical guidelines, such as Chompret and classic criteria, provide frameworks for identifying individuals at risk for P/LP TP53 variants; however, genetic counselors often encounter people with features concerning for LFS that do not clearly meet established criteria, creating challenges for risk assessment and testing decisions. We evaluated whether LFSPRO, a Mendelian, family-history-based model that estimates the individual's probability of harboring a deleterious TP53 variant, improves identification of individuals with LFS relative to guideline criteria. In a prospectively collected cohort of 178 probands who underwent clinical genetic counseling and germline TP53 testing, LFSPRO showed superior discrimination compared with Chompret criteria, with higher sensitivity (81% vs. 33%) and specificity (88% vs. 65%) and improved positive predictive values (PPVs: 0.53 vs. 0.14; negative predictive values NPVs: 0.96 vs. 0.85). Receiver operating characteristic analysis confirmed strong discriminatory performance (area under the curve AUC = 0.88). Calibration analysis using observed-to-expected ratios indicated good agreement between predicted and observed P/LP variant frequencies (observed/expected = 1.07). These findings demonstrate that LFSPRO outperforms traditional guideline-based criteria for identifying individuals with TP53 mutations in real-world clinical settings. By providing quantitative, well-calibrated TP53 P/LP variant probabilities rather than binary classifications, LFSPRO can enhance genetic counseling and support testing decisions, particularly for individuals who do not clearly meet existing criteria.