ATM Variants and Breast Cancer Risk in North Macedonia: Focus on the Regionally Enriched p.(Leu2492Arg) Variant

Background: ) gene are established moderate-risk factors for breast cancer (BC), however, population-specific variant spectra and the clinical significance of many missense variants remain incompletely characterized. Aims: variants in a large cohort of patients with BC from North Macedonia and compare it with that in the general population, with a particular focus on the frequency of the p.(Leu2492Arg) variant and its distribution relative to global genomic datasets. Study Design: This study was conducted as a retrospective case-control analysis. Methods: variants were analyzed in 1,211 patients with BC from North Macedonia using a targeted hereditary cancer gene panel. These findings were compared with those from 1,303 population-based controls analyzed by clinical exome or whole-exome sequencing. Results: = 0.086) and exhibited a markedly higher allele frequency in this population than in global databases. Conclusion: as a clinically relevant BC susceptibility gene in North Macedonia and highlight the population-specific enrichment of both PVs and the p.(Leu2492Arg) missense variant. The results emphasize the importance of using population-matched controls and regional genomic data for accurate risk assessment and variant interpretation.