Hereditary Breast Cancer in a Brazilian Referral Cohort: Germline Diversity and Genotype–Phenotype Associations
André Luiz Cicilini, Patrick Vinicius Cerqueira Batista, Sandrine M. Caputo, Viviane Primo Basilio de Souza, Solange Moraes Sanchez, Fabiana Baroni Makdissi, Marina de Brot, Marina de Assis da Escossia Fernandes, Beatriz Nelli Barbatto, Leticia Coelho de Mattos, Nathalia Machado Soldi, Flavia Cavalcanti Ballint, Débora Guilherme de Albuquerque e Rodrigues de Sousa, Eduarda Mirella da Silva Montiel, Lurick Rodrigues Soares, Thamilyn Yoshizaki Saruwatari, Sahlua Miguel Volc, Solange Maria Torchia Carvalho Castro, Giovana Tardin Torrezan, Dirce Maria Carraro, Alexandre Andre Balliero, Vladmir Cláudio Cordeiro de Lima, José Claudio Casali-da-Rocha, Elizabeth Santana dos SantosThe germline landscape of hereditary breast cancer has been characterized predominantly in populations of European ancestry, with limited evidence from populations with different demographic histories. We investigated germline diversity and genotype–phenotype associations in a single-center ambispective cohort at a tertiary referral cancer center in Brazil. Among 10,098 individuals who underwent germline genetic testing, 503 adults with invasive or microinvasive breast cancer met the predefined eligibility criteria and carried 514 pathogenic or likely pathogenic germline variants. Analyses assessed gene distribution, recurrent and founder variants, ecological diversity metrics, and associations with clinicopathological characteristics and survival outcomes. BRCA1 (31.6%) and BRCA2 (21.7%) were the most frequently altered susceptibility genes, followed by TP53 (13.1%), including the Brazilian founder variant TP53 p.R337H (10.7%). Diversity analyses indicated substantial heterogeneity beyond BRCA1/2. In exploratory unadjusted analyses, BRCA1-associated tumors more frequently exhibited triple-negative phenotype, high histological and nuclear grade, elevated Ki-67, and increased tumor-infiltrating lymphocytes, whereas tumors associated with BRCA2, ATM, CHEK2, and mismatch repair genes more frequently exhibited luminal phenotypes. Recurrent variants included alleles previously reported in different geographic and population contexts. Exploratory survival analyses detected no statistically significant differences among genetic groups within a five-year analytical horizon. These findings describe a heterogeneous germline spectrum and exploratory genotype–phenotype associations in a Brazilian cohort. Heterogeneous genetic testing coverage and the absence of individual genomic ancestry assessment limit interpretation; the findings should not be considered ancestry-specific or nationally representative. Further studies with uniform genetic testing and genomic ancestry assessment are warranted in broader Brazilian and Latin American cohorts.