Evaluation of Lynch syndrome risk models in a multicenter diverse population.

10597 Background: Lynch syndrome (LS) is the most common cause of hereditary colorectal cancer (CRC) with an increased CRC lifetime risk of 70-80%. LS affects 1:250 individuals and is caused by pathogenic variants in the mismatch repair (MMR) genes. Statistical prediction models such as MMRpro and PREMM5 are widely used to identify LS carriers. However, these models are trained and validated in mostly white populations, and there remains a gap in understanding their performance in Hispanic populations. The purpose of this study was to evaluate the performance of MMRpro and PREMM5 on a large Hispanic cohort from the Clinical Cancer Genomics Community Research Network (CCGCRN). Methods: We validated MMRpro and PREMM5 on 3,490 CCGCRN families, of which 1,122 are Hispanic and 2,062 Non-Hispanic. The two models were evaluated for discrimination using the C-statistic, calibration using the observed to expected ratio (O/E), and overall performance using the root Brier score and negative and positive predictive value (NPV/PPV) at the 5% carrier probability threshold. Evaluations were stratified by ethnicity, and 95% confidence intervals were obtained via bootstrapping for all measures. Results: The C-statistic is 0.90 for both MMRpro (95% CI: 0.88, 0.92) and PREMM5 (95% CI: 0.87, 0.92). When stratified by ethnicity, the C-statistics are 0.96 (95% CI: 0.94, 0.97) and 0.86 (95% CI: 0.83, 0.89) for Hispanics and Non-Hispanics, respectively, in MMRpro, and 0.96 (95% CI: 0.94, 0.97) and 0.84 (95% CI: 0.79, 0.88) in PREMM5. Both models underpredict mutation probabilities, with O/E ratios ranging from 1.79 to 1.96. At a 5% threshold, variations in PPV between Hispanics and Non-Hispanics are observed in both models: 0.72 (95% CI: 0.63, 0.80) and 0.43 (95% CI: 0.37, 0.50) in Hispanic and Non-Hispanic groups in MMRpro; 0.50 (95% CI: 0.43, 0.57) and 0.25 (95% CI: 0.20, 0.30) in PREMM5. We observe less variation and higher values in NPVs in both models. Conclusions: Overall, MMRpro and PREMM5 perform well in this cohort in predicting the probability of having a pathogenic variant in an MMR gene, with modest underprediction. While these results offer reassurance for the clinical use of MMRpro and PREMM5 in Hispanic populations, further validation studies in underrepresented racial and ethnic populations are crucial.