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

Area of Science:

• Genetics
• Oncology
• Population Genomics

Background:

• Germline pathogenic variants (PVs) in the ataxia-telangiectasia mutated (ATM) gene are recognized moderate-risk factors for breast cancer (BC).
• The specific spectrum of ATM variants and the clinical implications of missense variants are not fully understood across diverse populations.

Purpose of the Study:

• To determine the prevalence of ATM variants in North Macedonian BC patients.
• To compare ATM variant frequencies with the general population in North Macedonia.
• To investigate the frequency and distribution of the p.(Leu2492Arg) variant globally and within this cohort.

Main Methods:

• Retrospective case-control study analyzing 1,211 BC patients and 1,303 population controls from North Macedonia.
• Targeted hereditary cancer gene panel sequencing for cases; clinical exome or whole-exome sequencing for controls.
• Statistical analysis to compare variant frequencies and assess BC risk (odds ratio).

Main Results:

• Pathogenic ATM variants were found in 1.9% of BC cases versus 0.4% of controls (OR=5.02, p=0.0006), indicating a 5-fold increased BC risk.
• Six recurrent protein-truncating variants accounted for over 70% of PVs, suggesting regional enrichment.
• The p.(Leu2492Arg) missense variant was more common in cases (1.9%) than controls (1.1%) and showed higher frequency than in global databases.
• ATM variant carriers had a higher prevalence of HER2-positive tumors (OR=2.92, p=0.0189).

Conclusions:

• ATM is a clinically significant breast cancer susceptibility gene in North Macedonia.
• Significant population-specific enrichment of ATM PVs and the p.(Leu2492Arg) variant was observed.
• Accurate BC risk assessment necessitates population-matched controls and regional genomic data for variant interpretation.