Genetic tests that analyse many genes frequently identify variants whose effect on health is not yet known. These are called variants of uncertain significance (VUS). Understanding how they arise and how they should be managed is important for clinicians and families.
How Variants are Classified
Under the ACMG/AMP guidelines, germline variants are placed in one of five categories: pathogenic, likely pathogenic, uncertain significance, likely benign and benign. Classification weighs several lines of evidence, including population frequency, the predicted effect on the protein, functional studies, segregation in families, whether the variant arose de novo, and previous reports in affected individuals.
Why Uncertainty Arises
A variant is classified as uncertain when the evidence is insufficient or conflicting. This is more common in populations that are under-represented in genetic databases, including many South Asian populations, because there is less information about which variants are common and harmless.
Clinical Management
- A VUS should not be used on its own to make clinical decisions.
- Management should be based on the patient's clinical findings and family history.
- Testing parents and other affected relatives can help clarify the significance of a variant.
- Many variants are reclassified as new evidence emerges. Most reclassified VUS are downgraded to likely benign or benign.
Variants in Cancer Testing
In tumour profiling, somatic variants are classified using the AMP/ASCO/CAP tier system. Tier I variants have strong clinical significance, Tier II have potential clinical significance, Tier III are of unknown significance and Tier IV are benign or likely benign. Only Tier I and Tier II variants are used to guide treatment decisions.
The Role of Counselling
Pre-test counselling helps families understand that uncertain results are possible. Post-test counselling ensures that a VUS is neither over-interpreted nor ignored, and that families know the result may be updated in future.