Performance of LFSPRO TP53 germline carrier risk predictions compared to standard genetic counseling practice on prospectively collected probands

Genetic counseling and testing for germline mutations are essential for identifying individuals at increased risk for cancer. Pathogenic 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 likely pathogenic/pathogenic TP53 variants; however, genetic counselors often encounter patients 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 individuals probability of harboring a deleterious TP53 variant, improves carrier identification relative to guideline criteria. In a prospectively collected cohort of 182 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 predictive values (PPV 0.53 vs. 0.14; NPV 0.96 vs. 0.85). Receiver operating characteristic analysis confirmed strong discriminatory performance (AUC=0.88). Calibration analysis using observed-to-expected ratios indicated good agreement between predicted and observed carrier frequencies (Observed/Expected=1.07). These findings demonstrate that LFSPRO outperforms traditional guideline-based criteria for identifying TP53 mutation carriers in real-world clinical settings. By providing quantitative, well-calibrated carrier probabilities rather than binary classifications, LFSPRO can enhance genetic counseling and support testing decisions, particularly for individuals who do not clearly meet existing criteria.