Reclassification of missense variant pathogenicity using ClinGen recommendations for recalibrated PP3/BP4 in silico predictor score thresholds.

Purpose: To estimate the effect of ClinGen-calibrated variant effect predictor (VEP) score thresholds on clinically-reported missense variants of uncertain significance (VUS) reclassification using 2015 American College of Medical Genetics/Association for Molecular Pathology variant classification guidelines. Methods: Missense VUS were reported from clinically indicated genome-wide sequencing or targeted multigene panel testing. Variants were reclassified after integrating select recalibrated VEP pathogenicity scores within the existing 2015 American College of Medical Genetics/Association for Molecular Pathology guidelines. VEPs include VARITY, AlphaMissense, ESM1b, BayesDel, VEST4, REVEL, PolyPhen-2, and SIFT. Results: Overall median percentage of reclassified missense VUS was 5%. VARITY demonstrated the highest median percent reclassification of missense VUS at approximately 7%. VUS reclassifications from 7 of 8 VEPs demonstrated complete agreement when compared with VUS reclassifications from all other VEPs, except for VARITY which demonstrated a mean percentage agreement of 91%. ESM1b and SIFT demonstrated significantly higher proportions of VUS reclassifications to likely benign compared with likely pathogenic. There was no association between VUS reclassification and autosomal mode of inheritance; however, SIFT and VEST4 demonstrated significantly higher reclassifications of VUS from autosomal dominant genes versus autosomal recessive genes. Conclusion: Recalibrated VEP pathogenicity score thresholds modestly affect missense VUS reclassification. The included VEPs largely demonstrated equal VUS reclassifications to likely pathogenic or likely benign with near complete agreement in VUS reclassification between the included VEPs.