Curating the Clinical Genome 2024 ePoster Gallery-Using MAVE Functional Data for VUS Reclassification in MSH2

Using MAVE Functional Data for VUS Reclassification in MSH2

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The document discusses the use of Multiplexed Assays of Variant Effect (MAVE) functional data for the reclassification of variants of uncertain significance (VUS) in the MSH2 gene. By assessing single nucleotide variants in a gene, MAVEs provide loss of function scores that are ancestry-independent. The study included a diverse cohort of 12 patients with 11 distinct VUSs, with 4 variants being reclassified as likely benign using MAVE data. Notably, variants in patients of non-White ancestry were more likely to be reclassified. The study suggests using specific loss of function score cutoffs for reclassification, highlighting the potential for future classification of uncertain variants. The results emphasize the usefulness of MAVE data in VUS reclassification and call for larger cohort studies to extend this approach to other clinically relevant genes. The study successfully reclassified 4/11 MSH2 VUSs from the Brotman Baty Institute Clinical Variant Database, showcasing the ancestry-agnostic nature of MAVE data in this process. Overall, the document underscores the importance of functional data in addressing VUSs and the need for further research in this area.

Keywords

Multiplexed Assays of Variant Effect

MAVE functional data

variants of uncertain significance

MSH2 gene

loss of function scores

ancestry-independent

reclassification

specific loss of function score cutoffs

clinical variant database

functional data