Variant Interpretation and Variants of Uncertain Significance

What a VUS is

Everyone carries genetic variants, which are places where the DNA code differs between people. An individual genome has roughly 4 to 5 million of them. [1] Labs that run clinical genetic tests sort the variants they find into five groups: "pathogenic," "likely pathogenic," "uncertain significance," "likely benign" and "benign." [2] A variant of uncertain significance (VUS) is a change the lab found but could not place in either the harmful or the harmless group because the evidence is not yet enough. A VUS is not a positive result, and it is not a negative one either. This page is information only and is not medical advice. Individual gene records are in the Research Library.

How labs decide

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology published a process for placing variants into the five groups using several types of evidence, such as population data, computational data, functional data and segregation data (how a variant travels in a family). [2] Different labs can weigh that evidence differently. In a collaboration among four clinical laboratories, 88.3% of 6,169 variants that at least two labs had interpreted were initially concordant. After reassessment of a subset of the discordant ones, 87.2% were resolved, and the rest stayed different because the labs applied the guidelines differently. [3]

ClinVar, a public archive run by the US National Center for Biotechnology Information, collects variant classifications from many submitters. It shows both consensus and conflicting assertions of clinical significance and assigns a review status to each record, so users can judge how trustworthy a classification is. [4]

What happens to a VUS over time

A VUS can move. At one commercial laboratory, 7.7% of unique VUS were reclassified; of those, 91.2% were downgraded to benign or likely benign and 8.7% were upgraded to pathogenic or likely pathogenic. [5] Counting every reported VUS rather than each unique one, 24.9% were reclassified. [5] In other words, most reclassified VUS turned out to be harmless, but a minority did not, and many remain unresolved. Another prospective study found that reclassification rates differed by ancestry group. [6] See ancestry and population applicability.

What a VUS does not mean

• It does not mean a "moderate" risk. The lab simply cannot say yet.
• It is not a reason to change a medicine, a screening plan or a diet. Decisions about care belong with a genetic counselor or a doctor who has the full report and family history.

VUS can be hard on patients. Experts describe VUS results as a growing and long-term challenge for providers that have caused negative patient outcomes. [7] Yet in a study of 1,264 people tested with a 25- or 28-gene hereditary cancer panel, 35% had a VUS, and their distress scores were similar to those with negative results and lower than those of carriers of a pathogenic variant. [8]

Why VUS are more common in some tests and groups

In germline genetic testing, variants from understudied ancestries have been disproportionately classified as being of uncertain significance. [6] For related topics, see raw genetic data interpretation and clinical validity and clinical utility.