If you have had a genetic test—whether an exome, a gene panel, or whole genome sequencing—chances are your report includes one or more Variants of Uncertain Significance, commonly abbreviated as VUS. This is the most frequent classification and, at the same time, the one that raises the most questions.
The ACMG Classification System
The international ACMG/AMP guidelines (Richards et al., 2015) establish five categories for each genetic variant:
- Pathogenic (P) — directly causes or contributes to disease.
- Likely Pathogenic (LP) — strong but not conclusive evidence of pathogenicity.
- VUS — insufficient evidence to classify in either direction.
- Likely Benign (LB) — evidence suggests it is harmless.
- Benign (B) — clearly has no clinical effect.
Why Are There So Many VUS?
The more genes you analyse, the more VUS you will find. A typical exome may reveal hundreds of VUS; a whole genome, thousands. This is entirely normal and should not be a cause for alarm.
The reason is statistical: the human genome contains millions of variants relative to the reference, and for most of them there is not yet sufficient clinical evidence in either direction. Every year, thousands of functional and association studies are published that reclassify variants from VUS to pathogenic or benign.
What Should You Do with a VUS in Your Report?
1. Do Not Ignore It, but Do Not Over-Interpret It
Make a note of any VUS that appear in genes relevant to your clinical or family history. These are the ones most likely to be reclassified in the future.
2. Consult a Clinical Geneticist
A clinical geneticist can evaluate whether the VUS is relevant in your specific context: Do you have a family history? Does the phenotype match? Are segregation studies possible?
3. Take Advantage of Periodic Reanalysis
At OmicaLabs, all GenePortal reports are automatically updated whenever clinical databases (ClinVar, gnomAD) reclassify variants. What is a VUS today may be reclassified as benign—or pathogenic—within a year.
An Encouraging Fact
According to recent studies, approximately 90% of VUS that are reclassified turn out to be benign. Only a small percentage are reclassified as pathogenic, and when that happens, automatic reanalysis ensures you will not miss it.
If you have questions about any variant in your report, contact us or book an appointment with our clinical genetics team.