A Frequently Occurring MSH2 Variant in Middle Eastern and North African Patients With Lynch Syndrome: Evidence For a Possible Founder Variant

Document Type

Conference Proceeding

Publication Date

6-2026

Publication Title

Familial Cancer

Abstract

Background and Aim: Lynch syndrome (LS) is a common cause of hereditary colon, endometrial, and ovarian cancer. LS is caused by germline pathogenic variants (PVs) in the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) and EPCAM. Little is known about LS in Middle Eastern and North African (MENA) populations. We describe our institution’s experience with a unique MSH2 PV in a cohort of individuals with MENA ancestry. Methods/Clinical Presentation/Preliminary Data: Records of patients with LS and MENA ancestry seen in a high-volume cancer genetics center between January 2008 and March 2024 were analyzed. We reviewed genetic test results, cancer history, family history, and pathology. Results/Discussion/Project Plan and Timeline: A total of 483 LS patients were identified, of whom 60 (12.4%) had MENA ancestry. Of those, 53 individuals (88.3%) from 22 separate families harbored the same PV in MSH2, c.932delA (p.N311Tfs*20). This variant was only detected in our MENA LS population. Of the 53 individuals with this variant, 30 (56.6%) had at least one cancer diagnosis (17 colon, 12 endometrial, 7 renal/urothelial, 6 ovarian, 4 breast, 7 other) and 23 were unaffected. Of affected individuals, 16 (53.3%) had more than one cancer. The average age of colon cancer onset was 49.6 years, (26–72 y.o.). All 9 colon cancers with available MMR immunohistochemistry showed loss of MSH2/MSH6 protein expression. Amsterdam II criteria were met by 17 families (77.3%). Pancreatic cancer was present in close relatives in 6 families (27.3%). Additionally, 14 families underwent cascade testing (mean: 4 relatives, range: 1–13), identifying 25 “true negative” individuals. Conclusions/Requirements for Collaboration: This study is the first report of a recurrent MSH2 c.932delA PV in MENA patients with LS. This variant was seen exclusively in our MENA patients, and demonstrated a highly penetrant cancer phenotype. These findings suggest a possible LS founder variant in the MENA population. Further studies are needed to better characterize LS in this population.

Volume

25

Issue

2 Suppl

First Page

49

Comments

CGA-ICG (Collaborative Group of the Americas on Inherited Gastrointestinal Cancer) Annual Meeting, October 9-11, 2025, St. Louis, MO

Last Page

50

DOI

10.1007/s10689-026-00561-4

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