- Variant classification
- Discussing a Variant of Uncertain Significance with a laboratory
- Re-evaluating a VUS over time
Variant classification
A five-tier classification system is typically used to describe variants to a gene or DNA sequence (1). The laboratory performing a genetic test uses the classification system to evaluate a variant by gathering all of the information known about the variant. Variants with insufficient or conflicting evidence supporting disease association, which cannot be classified as ‘pathogenic/likely pathogenic’ (disease-associated), nor as ‘benign/likely benign’ (not disease-associated), are called Variants of Uncertain Significance (VUS). A VUS does not confirm a genetic diagnosis, and instead clinical decision-making relies on clinical correlation and diagnosis.(1)
Variants of Uncertain Significance may vary widely along a spectrum of suspected pathogenicity. Some may have a high level of supporting evidence where additional supporting evidence may cross the threshold to pathogenicity(2); In such instances, the testing laboratory may reclassify the VUS. Other VUSs have very little or conflicting evidence and require substantial amounts of evidence before a laboratory may consider reclassification.
Discussing a Variant of Uncertain Significance with a laboratory
Clinicians who receive a genetic test result reporting a VUS may consider discussing the classification with the laboratory. A clinician may also want to understand whether the VUS is leaning benign or leaning pathogenic in order to investigate the VUS further (2) or discuss it with a patient. In discussing a VUS classification with the laboratory, additional data may be informative (3, 4), such as:
- Providing the patient’s clinical and/or biochemical findings with the laboratory
- Considering additional biochemical, imaging, or functional testing for the patient
- Testing the parents or biological family members, when suggested by the laboratory
- Providing the relevant family medical history
- Finding literature reports or other patients with the same variant and similar phenotype
- Look for variant data in databases of documented genotype-phenotype relationships
- Considering data from available functional expression assays, research tests or
Re-evaluating a VUS over time
Over time, more evidence may become available suggesting that a variant is more/less likely to be disease-associated. In such instances, a VUS may be re-classified. For this reason, clinicians may consider re-evaluating uncertain genetic findings periodically with the laboratory. (3)