Whole genome profiling of 400 patients at risk for hereditary cancer in a Brazilian cohort

Abstract Hereditary cancer syndromes, caused by inherited genetic alterations, account for 5–10% of all cancers, posing substantial diagnostic and management challenges. Despite advances in next-generation sequencing technologies, access to genetic testing remains limited, particularly in low- and middle-income countries (LMICs), such as Brazil. Genetic heterogeneity and complex etiopathogenic patterns further complicate case resolution. This study enrolled genetically underrepresented admixed individuals at risk for hereditary cancer at a Reference Center for Rare Diseases in Salvador, Bahia, Brazil. A total of 400 individuals meeting hereditary cancer risk criteria underwent whole genome sequencing from whole blood as part of the Brazilian Rare Genomes Project. Clinical, demographic, and genetic data were jointly analyzed to investigate cancer predisposition. Most participants were female (95%), self-identified as brown/admixed (74.3%), and reported a personal history of breast cancer (74%). Pathogenic or likely pathogenic (P/LP) variants in hereditary cancer-related genes were identified in 23% of individuals, most frequently in BRCA1 (17.7%), BRCA2 (17.7%), MUTYH (6.3%), NF1 (5.2%), ATM (4.2%), and TP53 (4.2%) genes. Diagnostic conclusions were reached in 19% of cases with 7.8% of these harboring P/LP variants in two different genes. Inconclusive cases accounted for 26% of the cohort and included those with P/LP findings in genes with an unclear association to the patient’s cancer type, variants in heterozygous states for recessive conditions or variants of uncertain significance. The remaining 55% of cases were negative. Additionally, ACMG-recommended secondary findings were identified in 3.8% of patients. Notably, one patient carried a deep intronic variant that would have been missed by panel or exome sequencing. These findings highlight the genetic diversity in hereditary cancer syndromes and emphasize the need for expanded access to genetic testing and research to improve diagnostic outcomes.