Sequence Variants of Uncertain Significance: What to Do When Genetic Test Results Are Not Definitive

Clinical genetic testing for cancer predisposition syndromes often identifies DNA changes whose effects cannot be interpreted easily. These changes, often referred to as variants of uncertain significance (VUS), are not useful for clinical management. In contrast with clearly pathogenic mutations, VUS do not firmly diagnose a specific syndrome at the molecular level and cannot be used to identify with certainty which relatives are mutation carriers and which relatives are free of the syndrome. This article discusses the approach to evaluating VUS and how clinicians can play a key role in advancing the field to benefit all patients.