You may have seen the term “Variant of Uncertain Significance (VUS)” in your genetic report.
A VUS does not end the diagnostic journey. It keeps the diagnosis open.
What happens next may make all the difference.
A Variant of Uncertain Significance is not a failure.
It is often the most honest outcome of clinical-grade genomic testing.
A VUS may appear in a first exome report — including ours.
Because uncertainty is part of real medicine.
What happens next depends on clinical judgment.
Not all VUS are equal.
Some are strong candidate pathogenic variants.
Others are reported for completeness and are unlikely to explain the patient’s phenotype.
Recognizing the difference is part of clinical expertise.
FROM UNCERTAINTY TO ACTION
We do not force certainty.
We build a clinically defensible trajectory.
Clinical context integration
We interpret the variant within the complete diagnostic picture — not as an isolated laboratory finding.
Segregation strategy
When appropriate, we promote family testing to reduce uncertainty in a meaningful way.
Evidence calibration
Classification is not a mechanical process. The strength assigned to ACMG criteria may be refined according to the overall clinical evidence.
Mutational spectrum contextualization
Variants are interpreted within the known disease mechanism and mutational spectrum of each gene. This helps prevent biologically implausible classifications.
Long-term follow-up
For selected cases, genomic data may be re-analysed after 18–24 months using updated bioinformatic pipelines and newly available scientific evidence.
About this Clinical Insight
A Variant of Uncertain Significance (VUS) is one of the most common findings in Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS). This Clinical Insight explains what a VUS is, why it does not necessarily indicate disease, and how genetic variants are classified according to the ACMG guidelines. It also explores the role of clinical context, family segregation studies and evidence re-evaluation in the interpretation of uncertain variants. Rather than focusing on laboratory classification alone, this page highlights the role of clinical reasoning in managing diagnostic uncertainty and guiding appropriate genetic decision-making.