AbstractBackgroundVariant curation refers to the application of evidence‐based methods for the interpretation of genetic variants. Significant variability in this process among laboratories affects clinical practice. For admixed Hispanic/Latino populations, underrepresented in genomic databases, the interpretation of genetic variants for cancer risk is challenging.MethodsWe retrospectively evaluated 601 sequence variants detected in patients participating in the largest Institutional Hereditary Cancer Program in Colombia. VarSome and PathoMAN were used for automated curation, and ACMG/AMP and Sherloc criteria were applied for manual curation.ResultsRegarding the automated curation, 11% of the variants (64/601) were reclassified, 59% (354/601) had no changes in its interpretation, and the other 30% (183/601) presented conflicting interpretations. With respect to manual curation, of the 183 variants with conflicting interpretations, 17% (N= 31) were reclassified, 66% (N= 120) had no changes in their initial interpretation, and 17% (N= 32) remained with conflicting interpretation status. Overall, 91% of the VUS were downgraded and 9% were upgraded.ConclusionsMost VUS were reclassified as benign/likely benign. Since false‐positive and ‐negative results can be obtained with automated tools, manual curation should also be used as a complement. Our results contribute to improving cancer risk assessment and management for a broad range of hereditary cancer syndromes in Hispanic/Latino populations.