Building a Hereditary Cancer Program in Colombia: A Comprehensive Analysis of Germline Pathogenic and Likely Pathogenic Variants Spectrum in a Hispanic/Latino Population

Background: Limited research exists on cancer gene-associated syndromes beyond BRCA1 and BRCA2 in Latin America. Understanding the prevalence and spectrum of pathogenic/likely pathogenic variants (PVs) is crucial for advancing precision cancer medicine in the region. To address this gap, we assessed the prevalence of hereditary cancer syndromes (HCS) in Colombians with solid tumors and characterized the mutation spectrum.Methods: This national cancer hospital registry-based study focused on the molecular epidemiology of cancer patients included in the Colombia's largest Institutional Hereditary Cancer Program (April 2018 - June 2020). Patients aged ≥ 18 years with solid tumors referred for genetic counseling and meeting HCS criteria were admitted to the program and offered genetic testing. We calculated PVs and HCS prevalence by cancer type and gene. We elaborated on genotype-phenotype correlations of PVs in breast cancer genes and molecular subtypes, as well as reporting positivity rates stratified by different germline genetic testing criteria for breast cancer patients.Findings: We identified 216 PVs in 43 genes among 197 (26%) of 769 patients. 120 PVs were unique, and 33 were recurrent. 21% (160/769) had an autosomal HCS (159 dominant, one recessive), while 5% (37/769) were heterozygous carriers of PVs in autosomal recessive genes. 42% (321/769) had one or more variants of uncertain significance, and 33% (251/769) had negative results. HCS prevalence varied by cancer type (range 11% - 26%), with the highest observed for colorectal cancer. Six additional HCS were considered incidental findings. Triple-negative breast cancer subtype and bilateral presentation were the best predictors of an inherited breast cancer.Interpretation: Our study highlights a significant contribution of PVs in Colombian solid tumors patients, emphasizing the importance of genetic counseling and testing to support oncology practice in the region. It contributes to understanding the Colombian PVs spectrum in cancer genes.Funding: : Instituto Nacional de Cancerología, Bogotá, ColombiaDeclaration of Interest: The authors have no conflicts of interest to declare.Ethical Approval: The Scientific Committee of the INC-C approved the program as a Quality Improvement Project in 2017