Variants of uncertain significance: what they mean and when to consider retesting

A variant of uncertain significance (VUS) is a DNA sequence change for which there is currently insufficient evidence to classify it as either pathogenic (disease-causing) or benign. VUS reports are common — particularly in comprehensive multi-gene panel testing — and frequently cause uncertainty for both clinicians and patients. Understanding what a VUS means, and what it does not mean, is essential before communicating results.

Most variants identified by next-generation sequencing are rare or novel. The classification of a variant as pathogenic requires consistent evidence from multiple sources: population frequency data, computational predictions, functional studies, and observed co-segregation with disease in affected families. For the majority of rare variants — particularly those in genes where evidence is still accumulating — this evidence base does not yet exist. The more genes a panel covers, the higher the likelihood of encountering at least one VUS.

The most important communication principle is this: a VUS is not a positive result. Current classification guidelines (ACMG/AMP) are explicit that management decisions should not be based on a VUS finding alone. A VUS does not confirm hereditary risk, and it should not trigger prophylactic interventions, change surgical planning, or prompt cascade testing in relatives as though it were a pathogenic variant. The appropriate framing for patients is: 'We found a variant, but we do not currently have enough evidence to know if it is relevant to your health. We will monitor whether the evidence changes over time.'

Cascade testing for relatives is generally not recommended when the variant is a VUS. Testing a relative is only informative if the variant's significance is established; identifying the same VUS in an unaffected relative adds uncertainty rather than clarifying it. The exception is when cascade testing is being coordinated as part of a deliberate family study designed to generate co-segregation evidence to assist reclassification — and this should be done in the context of an active clinical genetics referral.

Reclassification happens, and it happens in both directions. Studies show that a meaningful proportion of VUS findings are reclassified over time — some to likely pathogenic or pathogenic, others to likely benign or benign. Clinicians should advise patients to maintain contact with the ordering service, as updated classifications will be issued when evidence changes. Most laboratories run active reclassification programmes and will notify the ordering provider if a clinically significant upgrade occurs.

Retesting should be considered when significant time has elapsed since the original test (particularly if panel design or guidelines have been updated), when new family history information emerges that could provide co-segregation data, or when the patient's clinical picture has evolved in a way that makes the variant's relevance more plausible. Advanced Consensus can assist with variant review, coordination with the original laboratory, and determining whether updated testing is indicated.