What is a Variant of Uncertain Significance (VUS)
A Variant of Uncertain Significance (VUS) is a genetic variant identified through genetic testing that cannot be clearly classified as either benign (not disease-causing) or pathogenic (disease-causing) based on the available evidence.
VUS are commonly reported in tests such as gene panels, Whole Exome Sequencing (WES), or Whole Genome Sequencing (WGS). These tests analyze large portions of the genome and detect many genetic differences between individuals.
In some cases, the scientific and clinical data available are not sufficient to determine whether a specific variant is associated with disease. When this happens, the variant is classified as a VUS.
Why do VUS occur in genetic testing
VUS arise because human genetic variation is extensive and not fully understood.
Each individual carries thousands of genetic variants, most of which are harmless. Distinguishing between benign variation and disease-causing mutations requires evidence that is not always available.
Several factors contribute to the presence of VUS:
- Limited knowledge of gene–disease relationships
- Incomplete or evolving genetic databases
- Lack of functional studies for many variants
- Absence of comparable cases in the scientific literature
- Insufficient family data for interpretation
As a result, some variants remain unclassified at the time of testing.
How common are VUS findings
Variants of Uncertain Significance are relatively common in genetic testing.
Their frequency depends on the type of test performed:
- Lower in targeted tests (single gene or small panels)
- Higher in large multigene panels
- Higher in Whole Exome Sequencing (WES)
- Highest in Whole Genome Sequencing (WGS)
The broader the analysis, the greater the number of variants detected, and therefore the higher the likelihood of identifying one or more VUS.
What does a VUS mean for patients
A VUS does not provide a definitive diagnosis.
It is neither a positive result (pathogenic variant) nor a negative result (benign variant). Instead, it reflects uncertainty in the interpretation of that specific genetic finding.
In clinical practice:
- A VUS should not be used alone to make medical decisions
- It does not confirm the presence of a genetic condition
- It does not exclude a genetic cause of disease
The clinical relevance of a VUS must be evaluated in the context of:
- The patient’s symptoms
- Medical history
- Family history
- Other laboratory findings
Can a VUS be reclassified
Yes, a VUS can be reclassified over time.
As new scientific data become available, a variant initially classified as uncertain may later be redefined as:
- Likely pathogenic or pathogenic
- Likely benign or benign
Reclassification depends on the accumulation of evidence, including:
- New cases reported in the literature
- Improved population databases
- Functional studies
- Family segregation analysis
This process can take months or years. In many cases, periodic re-evaluation of genetic data is recommended.
What should you do after a VUS result
After receiving a VUS result, further evaluation is usually recommended.
Typical next steps may include:
- Genetic counseling to interpret the result in context
- Clinical assessment of the patient’s condition
- Review of family history
- Possible testing of relatives (segregation studies)
- Follow-up over time and potential reanalysis
The appropriate course of action depends on the clinical scenario and should be guided by a qualified healthcare professional.
Further reading
For a clinical perspective on how uncertain genetic findings are interpreted in real cases: