Implementation of next-generation sequencing (NGS) for the genetic analysis of hereditary diseases has resulted in a vast number of genetic variants identified daily, leading to inadequate variant interpretation and, consequently, a lack of useful clinical information for treatment decisions. Herein, we present MARGINAL 1.0.0, a machine learning (ML)-based software for the interpretation of rare BRCA1 and BRCA2 germline variants. MARGINAL software classifies variants into three categories, namely, (likely) pathogenic, of uncertain significance and (likely) benign, implementing the criteria established by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP). We first annotated BRCA1 and BRCA2 variants using various sources. Then, we automatically implemented the ACMG-AMP criteria, and we finally constructed the ML model for variant classification. To maximize accuracy, we compared the performance of eight different ML algorithms in a classification scheme based on a serial combination of two classifiers. The model showed high predictive abilities with maximum accuracy of 92% and 98%, recall of 92% and 98% and specificity of 90% and 98% for the first and second classifiers, respectively. Our results indicate that using a gene and disease-specific ML automated software for clinical variant evaluation can minimize conflicting interpretations.
Keywords: ACMG-AMP guidelines; BRCA1/2 genes; cancer; genomics; germline; machine learning; rare variant interpretation; variant pathogenicity.