What is a variant of uncertain significance?

So far, we have focused on the classification and interpretation of pathogenic and benign variants. In the next steps, we will detail how to address variants of uncertain significance (VUS).

When classifying variants, one will often encounter variants of uncertain significance or VUS. These variants are defined as an alteration in the sequence of the gene, where it is unclear if the variation impacts gene function or clinical outcome. Very often, these variants are rare and understudied, meaning that there is too little information available to make a confident assessment of its impact. Your ability to evaluate a variant is only as good as the information you have available about that variant. Oftentimes, the lack of diversity of data in publicly available datasets makes it impossible to interpret and classify these variants.

VUS exist along a spectrum according to how much evidence is available to inform their involvement in disease (Figure 1). A “hot” VUS has a high level of supporting evidence and may be reclassified once additional information is obtained. Unfortunately, most VUS lack this type of compelling evidence.

Warm > Tepid > Cool > Cold and ice cold. Few (Hot) VUS are ultimately considered diagnostic. Warm and Tepid = Follow-up testing in parents may help with interpretation and Classifications can change over time. Most (Cool and Cold/ice cold) VUS are not suspicious. Clinical factors that influence interpretation of a VUS include: 1) pre-test probability for the associated genetic condition 2) Presence or absence of features that are relatively specific for the genetic condition.”> Click to enlarge

Figure 1. The gradient of VUS classification is based on available evidence. Source: Paediatric Child Health

According to international guidelines, a VUS should not be used in clinical decision-making. One cannot confirm or exclude a diagnosis, nor can management decisions be made based on this information. Therefore, VUS are not always included in clinical reports, as it is not always clear to the patient how to interpret this information.

It is important to remember that although we do not currently understand the clinical significance of a VUS, this can change as more information becomes available to aid the interpretation of the VUS.