Understanding genetic variants of uncertain significance.

Abstract

Paediatricians order many first-line genetic tests, including chromosomal microarrays and gene panels. These tests may identify variants of uncertain significance (VUSs). A basic understanding of this type of result is important for test interpretation and clinical management. VUSs can be easily misinterpreted by healthcare providers and families. A five-tier classification system is typically used to interpret variation at the DNA sequence or chromosome level (1,2). Variants with insufficient or conflicting evidence supporting disease association, such that they cannot be classified as ‘pathogenic/likely pathogenic’, nor as ‘benign/likely benign’, are VUSs. The presence of a VUS, even in a relevant gene or chromosome, does not confirm a genetic diagnosis. The interpretation of a genetic variant is informed by several factors. These include inherent characteristics like the frequency at which the variant is found in the general population, the prior observation of the variant in other individuals with similar presentations, and the predicted impact of the variant. The methods used and the limitations of the test, along with the specific policies of the laboratory, will determine if a given VUS is reported back to the ordering provider. Clinically, the pre-test suspicion for the associated genetic condition, and the overlap between the possible genetic condition and the patient’s features, are important considerations.