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

MSH2

Recurrent pathogenic MSH2 variant c.932delA (p.Asn311ThrfsTer20), suggesting a founder variant in the Iraqi and Chaldean population

Lynch syndrome is the most common cause of hereditary colorectal and endometrial cancer, but little is known about it in Iraqi and Chaldean populations and, more broadly, in Middle Eastern and North African populations. The authors analysed the records of a high-volume cancer genetics centre between January 2008 and March 2024: of 483 patients with Lynch syndrome, 60 (12.4%) reported Iraqi or Chaldean ancestry, and 53 of them (88.3%), from 22 unique families, carried the same pathogenic MSH2 variant, c.932delA (p.Asn311ThrfsTer20), which was detected only in this population. Twenty-eight of the 53 (52.8%) had at least one Lynch syndrome-related cancer (17 colorectal, 12 endometrial, 7 renal or urothelial, 6 ovarian and one sebaceous carcinoma), of whom 16 (57.1%) had multiple malignancies, and the mean age at colorectal cancer onset was 49.6 years. Fourteen families (63.6%) underwent cascade testing, which identified 31 carriers of this MSH2 variant in the cohort and 25 true negatives. The authors present this first report of a recurrent MSH2 c.932delA variant in Iraqi and Chaldean patients with Lynch syndrome as suggesting a putative founder variant, and state that further studies are needed to characterise Lynch syndrome in this population.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The signal is clear: 88.3% of Lynch syndrome patients of Iraqi or Chaldean ancestry carry the same variant, across 22 unique families, which argues for testing c.932delA first in a patient of this ancestry suspected of Lynch syndrome. The founder label nonetheless remains a hypothesis: the abstract reports no haplotype analysis, recruitment comes from a single cancer genetics centre, and the proportion of affected carriers (52.8%) cannot be read as penetrance in a series of patients seen in consultation. The operational value shows in cascade testing, carried out in 14 families, which identified 31 carriers and 25 true negatives.

Analysis by Dr Thibaut Benquey