e12513 Background: Hereditary cancer syndromes account for approximately 5–10% of all cancer cases. Germline pathogenic variants in BRCA1 and BRCA2 remain the most recognized causes of hereditary breast and ovarian cancer (HBOC); however, exclusive BRCA-centered testing may underestimate the genetic heterogeneity of cancer susceptibility, particularly in underrepresented populations. In Mexico, access to comprehensive genetic testing remains highly centralized, limiting diagnostic yield and equitable care. Methods: We conducted a retrospective analysis of 193 individuals with breast cancer, referred for hereditary cancer evaluation, from January 2023 to Decemeber 2025 in a single center Hospital General de Tijuana at Tijuana, Mexico (a city in the Mexico–US border region). All patients met NCCN criteria for genetic testing and were assed by the medical genetics department. Genetic testing included BRCA1/2 -only analysis in a limited number of cases and predominantly next-generation sequencing multigene panels (70 genes). Diagnostic yield and gene distribution were analyzed. Results: Among the 193 individuals tested, 33 (17.0%) carried pathogenic or likely pathogenic variants, 74 (38.3%) harbored at least one VUS, and 86 (44.6%) had negative results. Pathogenic variants in BRCA1 (n = 12, 36.4%) and BRCA2 (n = 13, 39.4%) accounted for 75.8% (25/33) of all positive findings. Importantly, 24.2% of pathogenic variants were identified in non-BRCA genes, including TP53, CHEK2, PALB2, BLM, BRIP1, and FLCN, highlighting clinically actionable diagnoses beyond BRCA1/2. Analysis of VUS demonstrated substantial genetic heterogeneity, with variants distributed across genes involved in DNA damage response and repair, mismatch repair, polymerase proofreading, and hereditary tumor syndromes. T he most frequently affected genes were APC (n = 7, 9.5%) and ALK (n = 5, 6.8%), followed by AXIN2 (n = 4, 5.4%). Variants in DNA damage response and repair pathways were common, including ATM, CHEK2, BRCA2, POLE, POLD1, NBN, and BLM. Additionally, alterations were observed in mismatch repair genes associated with Lynch syndrome. Conclusions: Our findings confirm that while BRCA1/2 remain the predominant contributors to hereditary cancer susceptibility, a significant proportion of clinically relevant diagnoses in this population would be missed without expanded multigene panel testing. The high burden of VUS highlights the critical need for variant reclassification strategies, functional validation, and population-specific genomic data. Decentralizing access to comprehensive genetic testing and strengthening local expertise in variant interpretation are essential to improving hereditary cancer care in Mexico and similar resource-limited settings.
Guadarrama-Orozco et al. (Thu,) studied this question.