The promises and pitfalls of automated variant interpretation: a comprehensive review.

Abstract

The interpretation of DNA variants enables personalized medicine through precise diagnosis and treatment selection. To address the challenges of manual interpretation, a wide range of automated tools has been created. This study evaluates these tools through a comprehensive analysis of their features, methodologies, and performance assessment against the interpretations of the ClinGen Expert Panel for 256 variants associated with cardiomyopathies, hereditary cancer, or monogenic diabetes. Although the tools demonstrated high accuracy for clearly pathogenic/benign variants, they showed significant limitations with variants of uncertain significance (VUS). Despite current advances in automation for variant interpretation, our findings show that expert oversight is still needed when using these tools in a clinical context, particularly for VUS interpretation.