Genetic Landscape of Lynch Syndrome in a High-Risk Serbian Cohort: Predominance of MLH1 Variants and Implications for Risk-Based Testing.

Germline pathogenic or likely pathogenic variants in mismatch repair genes, predominantly MLH1, followed by MSH2 and MSH6.

Data on the spectrum of Lynch syndrome variants in Slavic populations, including Serbia, remain limited. Between 2018 and 2025, 176 individuals were tested on the basis of Amsterdam or Bethesda criteria, validated risk prediction models and/or family history, using next-generation sequencing with the Illumina TruSight Hereditary Cancer panel and ACMG/AMP classification. A pathogenic or likely pathogenic mismatch repair gene variant was identified in 27 of 176 individuals (15.3%), associated with a positive family history of Lynch-related tumours (p = 0.0001). MLH1 was the most frequently affected gene (10.2%), ahead of MSH2 (4.0%) and MSH6 (1.1%), with no pathogenic PMS2 variants and no pathogenic sequence-level EPCAM variants detectable by this approach. Recurrent MLH1 variants were observed in several families and two previously unreported MLH1 variants were identified.

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The value of such series lies less in the overall yield, heavily dependent on selection by Amsterdam and Bethesda criteria, than in identifying recurrent MLH1 variants across several families in one population: replicated, such observations allow rapid targeted testing in relatives. The complete absence of PMS2 variants should be read as a technical as much as an epidemiological limitation, this gene being notoriously difficult with short-read sequencing because of its pseudogene, as should the absence of EPCAM variants, which the panel cannot detect at the level of large rearrangements. The two previously unreported MLH1 variants remain to be functionally documented before any use in genetic counselling.

Analysis by Dr Thibaut Benquey