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Background: Automation has been introduced into variant interpretation, but it is not known how automated variant interpretation performs on a stand-alone basis. The purpose of this study was to evaluate a fully automated computerized approach., Method: We reviewed all variants encountered in a set of carrier screening panels over a 1-year interval. Observed variants with high-confidence ClinVar interpretations were included in the analysis; those without high-confidence ClinVar entries were excluded., Results: Discrepancy rates between automated interpretations and high-confidence ClinVar entries were analyzed. Of the variants interpreted as positive (likely pathogenic or pathogenic) based on ClinVar information, 22.6% were classified as negative (variants of uncertain significance, likely benign or benign) variants by the automated method. Of the ClinVar negative variants, 1.7% were classified as positive by the automated software. On a per-case basis, which accounts for variant frequency, 63.4% of cases with a ClinVar high-confidence positive variant were classified as negative by the automated method., Conclusion: While automation in genetic variant interpretation holds promise, there is still a need for manual review of the output. Additional validation of automated variant interpretation methods should be conducted., (© 2022 Natera, Inc. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)