Variants of Uncertain Significance

A variant of uncertain significance (VUS) is a DNA change for which the available evidence is insufficient to call it either disease-causing or harmless. It is the middle tier of the standard five-category classification, and it represents not a finding about the patient's risk but a statement about the limits of current knowledge. VUS classifications are common and can be reclassified as evidence accrues.

Definition

A variant of uncertain significance is a sequence variant whose accumulated evidence is insufficient to classify it as pathogenic or benign, placing it in the central tier of the standardized classification framework pending further data.

Scope

The topic explains why the uncertain category exists, what distinguishes it from pathogenic and benign calls, how variants come to be reclassified over time, and the challenges that VUS findings pose for counseling and for laboratory reporting. It addresses the interpretive and communication problems of uncertainty rather than offering rules for clinical action on a VUS.

Core questions

• Why does an uncertain category exist between benign and pathogenic?
• What kinds of evidence move a variant out of the uncertain tier?
• How and when are VUS reclassified?
• Why are VUS findings challenging to communicate?

Key concepts

• Uncertain tier of classification
• Insufficient or conflicting evidence
• Reclassification over time
• Probability of pathogenicity
• Communication of uncertainty
• Non-actionability of a VUS

Mechanisms

A variant is classified as uncertain when the weighted evidence neither reaches the threshold for (likely) pathogenic nor for (likely) benign, or when the evidence is internally conflicting (Richards et al., 2015). Under the Bayesian reformulation of the criteria, the uncertain tier corresponds to a band of intermediate posterior probability of pathogenicity rather than a discrete biological state (Tavtigian et al., 2018). Because the classification reflects current evidence, accumulating data, such as new population frequency information, functional studies, additional affected families, or shared interpretations across laboratories, can shift a variant into the benign or pathogenic tiers; copy-number variants are similarly subject to uncertain calls under their own standard (Riggs et al., 2020).

Clinical relevance

A VUS is, by definition, not established as clinically actionable, and understanding this is essential to appraising and communicating genetic results without overstating or dismissing them. The topic describes what an uncertain classification means and how it can change; it is a reference account and does not direct clinical management of any specific variant.

Epidemiology

Uncertain classifications are frequent in clinical sequencing, particularly for broad tests and for genes or populations with sparse reference data; their frequency tends to decline over time for a given gene as shared evidence accumulates and variants are reclassified (Richards et al., 2015).

History

The explicit uncertain category was formalized as the middle of the five-tier ACMG/AMP scheme, giving laboratories a defined way to report variants that the evidence could not resolve (Richards et al., 2015). The subsequent Bayesian modeling clarified that this tier represents an intermediate probability rather than a fixed state, and that thresholds, not biology, separate it from the adjacent tiers (Tavtigian et al., 2018).

Debates

How should the uncertain band be bounded?

Where to set the probability thresholds that separate uncertain from likely benign and likely pathogenic affects how many variants are called uncertain, and quantitative modeling has been used to argue for more consistent boundaries.

Key figures

• Sue Richards
• Heidi Rehm
• Sean Tavtigian

Seminal works

• richards-2015
• tavtigian-2018

Frequently asked questions

Does a variant of uncertain significance mean a person has a disease?

No. It means the evidence is currently insufficient to say whether the variant is harmful or harmless. It is a statement about the limits of knowledge, not an established risk finding.

Can a VUS change classification later?

Yes. As new evidence accumulates, such as population data, functional studies, or shared laboratory interpretations, a variant can be reclassified toward benign or pathogenic.