Abstract A069: Characterizing genetic ancestry associated variation in lynch syndrome genes

Abstract Despite being one of the most common cancer predisposition syndromes, most individuals with Lynch Syndrome (LS) remain undiagnosed. LS increases an individual’s lifetime risk of colorectal and endometrial cancer to 40-60%, representing a population in critical need of increased clinical surveillance. Underdiagnosis of LS is partly due to low rates of genetic testing, an issue especially relevant for underrepresented groups experiencing structural barriers to accessing genetic testing. Previous studies identified higher rates of variants of uncertain significance among groups of non-European ancestries, limiting interpretation of germline testing results in these populations. By characterizing ancestry-associated variation in LS genes, we aim to identify populations associated with increased prevalence of LS to better inform testing strategies to diagnose high-risk individuals. In this study, we examined germline whole genome sequencing data from 413,843 individuals in the All of Us biobank. 46% of this cohort were of predominantly non-European ancestry (19% African [AFR], 17% American Admixed [AMR], 2% East Asian [EAS], 10% other), representing one of the most genetically diverse cohorts in which to study LS population prevalence. We identified carriers of pathogenic variants in LS genes through analysis of single nucleotide polymorphisms, insertions, deletions, and structural variants. We applied the phecodeX phenotyping algorithm to linked electronic health record data to identify individuals diagnosed with endometrial, colorectal, and other LS-associated cancers. Our analysis identified 1,399 individuals with pathogenic or likely pathogenic variants previously annotated in ClinVar across the 5 LS genes. Among the 1160 carriers with linked electronic medical records, 15% had a LS related cancer diagnosis compared to 6% of age, ancestry, and sex matched controls. The cohort of pathogenic variant carriers was overrepresented for individuals of European (EUR) ancestry and underrepresented for individuals of AMR and AFR ancestries, reflecting ancestry biases within ClinVar annotations. Conversely, among carriers of variants of uncertain significance, EUR ancestry individuals were underrepresented while AMR and AFR ancestries were overrepresented. We found no significant differences in the frequency of predicted loss of function structural variants between genetic ancestries. Overall, 1 out of every 295 All of Us participants with whole genome sequencing data available is a LS gene pathogenic variant carrier. This prevalence was different by genetic ancestry (proportions test, p = 3.761e-14) with individuals of South Asian ancestry having the highest prevalence and individuals of Middle Eastern ancestry having the lowest. In conclusion, our study aims to determine the prevalence and variation of disease risk relevant germline genetic variation in LS genes across the genetic ancestry spectrum. By achieving these objectives, we anticipate enriching understanding of LS across diverse genetic backgrounds and informing targeted testing strategies. Citation Format: Devin A. Gee, Nyasha Chambwe. Characterizing genetic ancestry associated variation in lynch syndrome genes [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A069.