Understanding the landscape of hereditary breast and ovarian cancer testing in Brazil

Next-generation sequencing (NGS) is essential for hereditary cancer diagnostics, as it detects single-nucleotide variants (SNVs), INDELs, and structural variants (SVs). Following ASCO recommendations for comprehensive sequence and structural analysis, we retrospectively analyzed a 25-gene NGS panel from 5,000 unrelated individuals, with or without personal history of cancer, to characterize the germline mutational spectrum associated with hereditary breast and ovarian cancer (HBOC). Among the participants, 12.7% carried pathogenic or likely pathogenic (P/LP) variants, predominantly comprising SNVs. A positive result was identified in 14% of individuals with a cancer diagnosis and in 7.5% of unaffected individuals. Most P/LP SNVs were identified in BRCA1/2, CHEK2, TP53, ATM, and PALB2. Structural variants accounted for 7.6% of all P/LP findings and were predominantly identified in BRCA1/2 and ATM. Detection rates varied across tumor types, with more precise estimates observed in larger subgroups such as breast and ovarian cancer. Estimates derived from less frequent tumor types were associated with greater uncertainty due to smaller sample sizes. Variants of uncertain significance were identified in 25% of tests. This largest Brazilian HBOC cohort to date highlights that multigene panels identify P/LP variants even in unaffected individuals. These findings highlight the importance of incorporating SV detection into routine testing strategies and support efforts to expand access to genetic testing and counselling in Brazil.