Beyond Uncertainty: Using Functional Assays for Clinical Variant Classification

This presentation demonstrates how MAVE functional data can be translated into disease-specific functional evidence for clinical variant classification. It is framed around a BAP1 variant of uncertain significance (VUS), and presents different functional assay types, the ClinGen SVI framework for evaluating assay validity, calculating likelihood ratios using appropriate reference sets, and applying calibrated functional data as evidence for variant classification. 

The presentation is adapted from a workshop that was presented at the 2026 American College of Medical Genetics and Genomics (ACMG) annual meeting. It is also available as supplemental material for the pre-print manuscript titled "Phenotype-Specific Recalibration of MAVE Data Enables Repurposing of BAP1 Functional Assays for Küry-Isidor Syndrome": doi: https://doi.org/10.64898/2026.05.15.26352805