Abstract
<jats:title>ABSTRACT</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p> The ClinGen ENIGMA <jats:italic>BRCA1</jats:italic> / <jats:italic>BRCA2</jats:italic> Variant Curation Expert Panel (VCEP) has adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) framework into gene-specific specifications. However, applying these specifications manually remains labor-intensive and prone to inconsistency, requiring integration of population, computational, functional, and clinical evidence through gene-specific decision trees and a points-based classification system. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p> We developed HECTOR (HEreditary Cancer varianT Online Reclassifier), a free web-based tool that implements the complete ENIGMA VCEP v1.2 specifications for <jats:italic>BRCA1</jats:italic> and <jats:italic>BRCA2</jats:italic> . HECTOR automatically populates all evidence codes derivable from public data, routes curator-dependent evidence to a manual input layer and returns a transparent five-tier classification with code-level evidence. We validated HECTOR against two independent reference datasets: the 143-variant ENIGMA Evidence Repository, used as a clinical-grade reference standard, and 134 manually curated in-house variants of uncertain significance (132 unique variants). HECTOR was then applied to the complete ClinVar <jats:italic>BRCA1</jats:italic> / <jats:italic>BRCA2</jats:italic> catalog (n = 34,077). </jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>At the criterion level, HECTOR exactly reproduced 326 of 413 VCEP-assigned criteria (78.9%), with discordance arising predominantly from curator-dependent evidence rather than implementation errors. In an independent cohort of 134 manually curated in-house variants, HECTOR was fully concordant with expert consensus at the classification level and, even without auto-populated likelihood-ratio evidence, resolved more variants to a definitive classification than two generic ACMG/AMP classifiers. Across ClinVar, HECTOR classified 33,913 variants. Agreement with definitive ClinVar classifications was 96.7% for pathogenic variants and %72.7 for benign variants overall. Among variants for which HECTOR generated a definitive classification, directional concordance reached 99.7% for pathogenic and 99.9% for benign variants. HECTOR also resolved a substantial proportion of variants classified as uncertain (67.3%) or conflicting (88.7%), predominantly toward benign classifications.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p> HECTOR provides a faithful, transparent implementation of the ENIGMA VCEP v1.2 specifications for <jats:italic>BRCA1</jats:italic> and <jats:italic>BRCA2</jats:italic> , enabling rapid, standardized, and reproducible application of gene-specific variant classification guidelines while reducing the burden of manual curation. </jats:p> </jats:sec>