Broad germline variant spectrum revealed by whole-exome sequencing in an underrepresented Latin American population with hereditary breast cancer.

backgroundHereditary breast cancer (BC) accounts for a significant proportion of BC cases, yet germline variant interpretation remains limited in underrepresented populations such as those from Latin America. Most available genomic reference data derive from European and North American populations, constraining variant interpretations and clinical decision-making in other regions.

methodsWe performed whole-exome sequencing in 140 Chilean patients with clinically suspected hereditary BC. Germline variants were analyzed across canonical BC predisposition genes recommended by current NCCN guidelines and an extended set of additional cancer susceptibility genes. Variants were annotated and manually classified following ACMG/AMP guidelines, incorporating ClinGen gene-disease validity resources and cancer-specific CanVIG consensus recommendations.

resultsExpanded gene analysis resulted in an increased detection of pathogenic and likely pathogenic variants (~ 18% to ~ 24%) and reduced the proportion of patients with negative genetic results compared with canonical gene analysis alone. Pathogenic variants were most frequently identified in BRCA1 and BRCA2, followed by additional cancer susceptibility genes, with truncating variants representing the predominant alteration type. Exploratory analyses revealed a broad distribution of pathogenic variants across BRCA1 and BRCA2 gene regions.

conclusionsThis study provides a comprehensive overview of the germline variant spectrum in Chilean patients with suspected hereditary BC and demonstrates the added value of extended gene analysis beyond canonical predisposition genes. These findings contribute to population-specific genomic data and support efforts to improve variant interpretation and equitable implementation of genomic medicine in underrepresented populations.