Approach to the patient with a variant of uncertain significance on genetic testing

Establishing a genetic diagnosis may lead to major health benefits for the patient and their wider family, but is dependent on the accurate interpretation of test results. The processes of variant interpretation are by their nature imprecise such that the potential for uncertain test results (i.e., variant(s) of uncertain significance [VUS]) are an inevitable consequence of genomic testing. With an increased responsibility for diagnostic testing in the hands of the specialty physician (e.g., endocrinologist) rather than clinical geneticist, it is essential that they are familiar with the possible outcomes of testing including an understanding of the VUS category. While uncertainty is endemic to many aspects of clinical medicine, receiving a VUS result may pose a considerable challenge to both the clinician and the patient. In this article, a framework to support decision-making when confronted with a VUS variant is provided, focusing on the key components of the genetic testing pathway. This highlights the importance of assessing the VUS result in the context of the clinical presentation and genetic testing strategy, the value of multidisciplinary team working and ensuring good communication with the patient.

Automated summary

Establishing a genetic diagnosis is beneficial, but accurate interpretation of test results is crucial. Uncertain VUS results pose challenges for clinicians and patients. This article provides a decision-making framework, emphasizing the importance of evaluating VUS results.