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.