What is a variant of uncertain significance (VUS), and how should it be managed clinically?

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A variant of uncertain significance is a genetic change whose impact on disease risk isn’t yet known. It sits in between clearly pathogenic and clearly benign, and its classification can change as more evidence becomes available. Clinically, you should not alter management based on a VUS alone. Instead, continue with standard risk assessment and surveillance derived from the patient’s personal and family history and any definitively pathogenic results, not the uncertainty of the VUS. Communicate to the patient that this variant’s significance is unclear, and plan for periodic re-evaluation as new data emerge. Collect segregation information in families and reanalyze the variant over time; it may be reclassified as benign/likely benign or pathogenic/likely pathogenic with additional evidence. This approach avoids unnecessary interventions while allowing updates as knowledge evolves.