Lynch Syndrome-Associated Variants and Cancer Rates in an Ancestrally Diverse Biobank.

Purpose: Limited data are available on the prevalence and clinical impact of Lynch syndrome (LS)-associated genomic variants in non-European ancestry populations. We identified and characterized individuals harboring LS-associated variants in the ancestrally diverse Bio Biobank in New York City.

Patients And Methods: Exome sequence data from 30,223 adult Bio participants were evaluated for pathogenic, likely pathogenic, and predicted loss-of-function variants in , , , and . Survey and electronic health record data from variant-positive individuals were reviewed for personal and family cancer histories.

Results: We identified 70 individuals (0.2%) harboring LS-associated variants in (n = 12; 17%), (n = 13; 19%), (n = 16; 23%), and (n = 29; 41%). The overall prevalence was 1 in 432, with higher prevalence among individuals of self-reported African ancestry (1 in 299) than among Hispanic/Latinx (1 in 654) or European (1 in 518) ancestries. Thirteen variant-positive individuals (19%) had a personal history, and 19 (27%) had a family history of an LS-related cancer. LS-related cancer rates were highest in individuals with variants (31%) and lowest in those with variants (7%). LS-associated variants were associated with increased risk of colorectal (odds ratio [OR], 5.0; = .02) and endometrial (OR, 30.1; = 8.5 × 10) cancers in Bio Only 2 variant-positive individuals (3%) had a documented diagnosis of LS.

Conclusion: We found a higher prevalence of LS-associated variants among individuals of African ancestry in New York City. Although cancer risk is significantly increased among variant-positive individuals, the majority do not harbor a clinical diagnosis of LS, suggesting underrecognition of this disease.