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Variants of Uncertain Significance

Genomic tests can identify different types of variants within a gene, including those that are benign, pathogenic, or those with unknown or unclear effects.

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

  • A variant may be rare or novel, with insufficient data about its effects on the function of the gene and its relationship to disease.
  • Data about the effect of the variant on the gene may be conflicting.

While it is tempting to believe that variants identified in genomic testing contribute to disease risk, a VUS is not a clinically useful result. Changes in management based on the finding of a VUS are not recommended. If you have questions about a VUS result, you can discuss them with the genetic expert or 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.

 

Important points to discuss with patients before testing

 

Ideally, the likelihood of VUS results should be discussed with the patient before genomic testing. This is especially true in exome testing, where the likelihood of detecting multiple VUS is high and is a standard part of the informed consent process with the genetic expert.

Patients should be aware that:

  • Genetic variants are commonly reported.
  • Genetic variants may be associated with a disease or may be benign, with no clinical impact.
  • Relatives are not typically offered testing for a VUS.
  • Genomic testing is a rapidly evolving field and some variants have not yet been classified.
  • Reclassification of a VUS may change over time, and many will be reclassified as benign.

It is important to note that not all test reports will include VUS. Whether or not a test will detect and report out VUS can be determined by contacting the lab.

See the factsheet on Variant Classification and Reanalysis in Exome Testing for more information on how variants are classified and reclassified over time.