Whole-genome profiling of hereditary cancer risk in a highly admixed cohort from Northeast Brazil: clinical, genomic, and ancestry findings

Hereditary cancer syndromes account for 5–10% of all cancers, yet access to genetic testing remains limited in many low- and middle-income countries, including Brazil. The contribution of clinical and population factors to diagnostic outcomes remains poorly understood in admixed populations. This study investigated the socio-demographic, clinical, and genomic characteristics of 400 individuals at risk for hereditary cancer recruited at a Reference Service for Rare Diseases in Salvador, Bahia, Brazil, who underwent germline whole-genome sequencing through the Brazilian Rare Genomes Project. Participants were predominantly female (94.5%), self-identified as Brown (74.3%), and had a personal history of breast cancer (73.6%). Pathogenic or likely pathogenic variants in hereditary cancer-related genes were identified in 23% of individuals, and a conclusive molecular diagnosis was established in 19%. Inconclusive results accounted for 26% of cases, while 55% showed no clinically relevant variants. The most frequently affected genes were BRCA1 , BRCA2 , MUTYH , NF1 , ATM , and TP53 , and a deep intronic NF1 variant illustrated the ability of whole-genome sequencing to detect relevant noncoding variants. Genetic ancestry analyses confirmed the admixed background of the cohort and showed significant differences in ancestry proportions across self-reported racial groups. However, neither self-reported race/ethnicity nor genetic ancestry was associated with diagnostic yield or variant classification. Diagnostic yield varied according to clinical presentation and was highest in individuals with well-characterized syndromic conditions. These findings suggest that diagnostic outcomes were more closely related to clinical presentation than to genetic ancestry or self-reported race/ethnicity, supporting broader implementation of genomic medicine within public healthcare systems.