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Simple Summary: Lynch syndrome (LS) is an autosomal dominant disorder linked to increased risks of colorectal and endometrial cancers, caused by pathogenic variants in MMR genes (MLH1, MSH2, MSH6). In a cohort of 42,828 participants from the Taiwan Precision Medicine Initiative (TPMI), 89 individuals carried MMR gene variants: 25% MLH1, 53% MSH2, and 22% MSH6, with a prevalence of 1 in 481. Cancer incidence rates were 40.9% for MLH1, 29.8% for MSH2, and 40% for MSH6 carriers. Colonoscopy screening revealed no significant differences in polyp prevalence compared to controls. The study underscores the need for improved LS diagnosis and surveillance in the Taiwanese population. Lynch syndrome (LS) is an autosomal dominant disorder characterized by increased risks of colorectal and endometrial cancers. LS is defined by pathogenic variants in mismatch repair (MMR) genes, including MLH1, MSH2, and MSH6. Data on the prevalence and associated cancer risks of LS in the Han Chinese population remain limited. In this study, using a broad biobank approach through the Taiwan Precision Medicine Initiative (TPMI), we identified LS-associated MMR gene variants within a cohort of 42,828 participants from a Taiwanese medical center. A total of 89 individuals were found to carry pathogenic MMR variants: MLH1 (n = 22, 25%), MSH2 (n = 47, 53%), and MSH6 (n = 20, 22%). The overall prevalence of MMR variants was calculated, and cancer incidence rates among carriers were determined. The prevalence of MMR variants in the study population was 1 in 481. The distribution of MLH1, MSH2, and MSH6 variants were 24.7%, 52.8%, and 22.5%, respectively. Cumulative cancer incidence rates of carriers were 40.9% for MLH1 carriers, 29.8% for MSH2, and 40% for MSH6. Among the 19 individuals who underwent colonoscopy screening, the prevalence of polyps was similar to that of the control group (adenoma detection rate: 32% vs 26%, p = 0.585). A meticulous analysis of the detected polyps in seven participants, considering factors such as location, size, morphology, and pathological features, showed no significant differences from controls. A significant cancer risk is associated with LS-related MMR variants in the Taiwanese population. The apparent under diagnosis of LS highlights the urgent need for enhanced surveillance and genetic counseling in this demographic. Our findings suggest that adjustments in the current screening protocols may be warranted to better identify and manage at-risk individuals. [ABSTRACT FROM AUTHOR]