A frequently occurring MSH2 variant in Iraqi and Chaldean patients with Lynch syndrome: evidence for a putative founder variant.

Lynch syndrome (LS) is the most common cause of hereditary colorectal and endometrial cancer. LS is caused by germline pathogenic variants (PV) in the mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and EPCAM. Little is known about LS in Iraqi/Chaldean and broader Middle Eastern and North African populations. We describe our institution's experience with a unique MSH2 PV in a cohort of Iraqi/Chaldean patients. Records of patients with LS and Iraqi/Chaldean ancestry seen in a high-volume cancer genetics center between January 2008 and March 2024 were analyzed. A total of 483 LS patients were identified, of whom 60 (12.4%) reported Iraqi/Chaldean ancestry. Of those, 53 individuals (88.3%) from 22 unique families harbored the same PV in MSH2, c.932delA (p.N311Tfs*20) and were analyzed in this study. This variant was detected only in our Iraqi/Chaldean population. Of individuals with this variant, 28 (52.8%) had at least one LS-related cancer diagnosis (17 colorectal, 12 endometrial, 7 renal/urothelial, 6 ovarian, one sebaceous carcinoma), of whom 16 (57.1%) had multiple malignancies. The average age of colorectal cancer onset was 49.6 years. Additionally, 14 families (63.6%) underwent cascade testing, identifying 31 of the MSH2 carriers in this cohort and 25 true negatives. This is the first report of a recurrent MSH2 c.932delA PV in Iraqi/Chaldean patients with LS. These findings suggest a putative LS founder variant in the Iraqi/Chaldean population, and further studies are needed to characterize LS in this population.