Understanding variants of uncertain significance in somatic cancer panel testing

Genetic variants are abundant in tumor cells; some are benign, while others disrupt or alter the function of the gene and affect tumor growth. Somatic cancer panel testing often detects variants in cancer cells that have unknown or unclear effects on the cancer cells. These are called variants of uncertain significance, or VUS. In the cancer setting, they are also sometimes referred to as variants of unknown therapeutic significance.

The clinical significance of a variant may be uncertain for several different reasons:

• A variant may be rare or novel, with very little data about its effects on the function of the gene.
• Even when a variant is clearly disruptive of the gene, there may not be enough evidence to confirm its role in driving tumor growth.
• Data about the effect of the variant on the gene and on tumor growth may be conflicting.
• Evidence may indicate that a variant is an important therapeutic target in one type of cancer, but not enough is known about its role in other types of cancer.

While it is tempting to believe that variants found in cancer cells could be contributing to progression of the cancer, a VUS is not a meaningful result. Changes in management based on the finding of a VUS are not recommended. If you have questions about the VUS result, you may call the laboratory to ask for any information they might have about it and why it is classified as a VUS. In some cases, a VUS may be reclassified as "actionable" as new data is obtained.

How should you explain a VUS to your patient?

Ideally, the possibility of a VUS should be discussed with the patient before a somatic cancer panel is ordered. Important points to discuss with patients are:

• Genetic variants can be either harmful or harmless.
• Tumor genetics is a new field, and some variants have not been classified.
• A VUS is an uninformative result that does not yield any information about targeted therapies.

May 2020