Germline variation across breast cancer predisposition genes: whole-exome evidence

Abstract Understanding the population-level spectrum of genetic variation in cancer-associated genes is critical for improving variant interpretation and informing precision medicine. However, most hereditary cancer research has been conducted in populations specific cohorts, with underrepresentation of Middle Eastern populations in global genomic databases. These important data can be enriched with studies from different underrepresented ethnic groups to ensure diversity and inclusion. This study aims to characterize pathogenic and likely pathogenic variants in selected cancer-associated genes in a large Saudi population cohort. The whole-exome sequencing (WES) of 11,093 individuals without documented cancer diagnosis from different parts of the Kingdom of Saudi Arabia (KSA), was analyzed to identify protein-altering variants across 20 breast cancer-associated genes. Variant annotation and classification were performed using established databases and interpreted according to American College of Medical Genetics and Genomics (ACMG) guidelines. A total of 217 variants were identified across the 20 genes analyzed. Of these, 156/217 (71.9%) occurred in high- and moderate-risk breast cancer susceptibility genes. Most of the variants were detected in genes associated with hereditary breast cancer susceptibility and DNA repair pathways such as BRCA1 , BRCA2 , ATM , CHEK2 , PTEN , and PALB2 . A substantial proportion of the variants were not currently reported in ClinVar. Most variants were found in a heterozygous state, consistent with carrier status in the general population. This study provides population-level insights into the prevalence of pathogenic variants in breast cancer-related genes in the Saudi population. The findings highlight the importance of population-specific genomic data to improve variant interpretation and support the development of precision medicine and genetic screening strategies in underrepresented populations.