Variants of Uncertain Clinical Significance

What is a Variant of Uncertain Clinical Significance?

A variant of uncertain clinical significance (VUS) is a DNA change that is not yet fully understood. The VUS may be unique or may have been found in other individuals or families.

Sometimes a lot of work may have been done to determine the effect of that specific DNA change. However, to classify the variant as likely pathogenic (Class 4) or likely benign (Class 2), you need to be at least 95% sure. And that's a pretty high bar!

To classify a DNA change as Pathogenic (disease causing) you have to be 99% sure!

A cooking example may help to explain...

Imagine you are baking a cake and the recipe says "Bake for 30 minutes". If you change 30 minutes to 300 minutes the cake isn't going to work at all. These are called Class 4 or Class 5 variants and they almost always cause problems.

If you change 30 minutes to 29 minutes....who cares? Half the cooks take the cake out at 29 minutes, half at 30 and the cake is just fine. These are Class 1 or Class 2 variants. If they are common, they are called polymorphisms.

But what does 27 minutes mean or 25 minutes? Does the cake work or not?

Scientists have ways of trying to sort out this out. The first is to see if the change occurs in an important part of the recipe (such as the part of a gene that codes for a functional domain). Or perhaps every recipe ever seen is always written that way. This is called evolutionary conservation. If it's the same in every creature that has that gene, that's called highly conserved. It can be a clue that a mistake here may have consequences.

Scientists can check to see if a similar change has been found by looking in international databases, such as ClinVar. For our cake: if we know that 26 minutes causes problems, 25 minutes almost certainly will too.

Published studies on the genetic causes of cancer can be helpful. For example, maybe the variant is only ever found in people who have had cancer. Or, maybe it's evenly spread between those with and those without cancer.

In our cake example, you could ask a chef to read your recipe and tell you whether they think it will work or not. For DNA, scientists turn to in silico protein prediction tools. Things like size, shape and charge of an amino acid or how a protein folds up can all affect how a protein may function. In silico tools use computers to model how the change in the DNA of a gene will affect the function of the protein made by that gene.

Lastly, you can make the cake. That is, you can perform functional studies. These studies can be expensive and may take many months to perform. But, even if the protein seems to work in the lab, it doesn't necessarily mean it will in work in a person.

So... even after a lot of work, the effect of a variant may remain clinically uncertain.

What do we do if we find a variant of uncertain clinical significance?

By definition, the effect of a variant of uncertain clinical significance (VUS) on a person's cancer risk is unknown.

If we don't know what a change means in the person tested, especially if they were the one who had cancer, we can't know what it means for their children or siblings. That's why there's no testing for variants of uncertain clinical significance in blood relatives. It wouldn't alter their management and can lead to anxiety and confusion.

In some families, testing of a distant relative who has had cancer may be performed. This segregation testing is a research technique and is used to see if the VUS is tracking with cancers in the family. Functional studies, where proteins made from the damaged gene are studied, may also be conducted.

If a VUS is found, screening and management is based on the personal and family history. That's why seeing a Genetic Oncologist to order the testing is a good idea