Your genetic report names a variant of uncertain significance, or VUS. You finally have a specific finding, but the report stops short of saying that it explains the symptoms or family history. That can feel frustrating. The useful next step is to separate what was found from what is known about its effects.
A VUS is a DNA change for which the available evidence does not support a clear pathogenic or benign classification. It is not a confirmed genetic diagnosis, and the word “uncertain” does not mean a precisely calculated 50:50 chance of harm.
What is uncertain: the measurement or the meaning?
Often, the laboratory can reliably detect a sequence change but cannot yet establish its relationship to disease. There may be few affected people described, insufficient functional evidence or conflicting observations. MedlinePlus explains inconclusive genetic results and why they cannot confirm or rule out a diagnosis.
Technical uncertainty is a separate issue. If a report says that a finding needs confirmation, ask what the confirmation would establish. Repeating the measurement may show that a variant is genuinely present without resolving whether it causes disease.
| Question | What a VUS does not establish |
|---|---|
| Was a DNA change detected? | Detection alone does not establish its biological or clinical effect. |
| Can this particular change cause the relevant condition? | The gene’s name alone cannot answer this. |
| Does it explain this person’s findings? | A candidate result must still fit the clinical and inheritance evidence. |
Example 1: a BRCA2 VUS is not a positive hereditary cancer result
Fictional teaching example. A woman with a family history of breast cancer receives a report listing a BRCA2 VUS. She asks whether the result means that she has the same inherited risk as someone with an established pathogenic BRCA2 variant.
It does not establish that conclusion. NCI explains that a VUS usually should not determine medical decisions. Her own history and family pattern may still justify clinical assessment or screening, but those decisions have a different evidential basis. See the NCI inherited cancer testing fact sheet.
A helpful question is: “Which parts of my care plan are based on my history, and would any recommendation change if this VUS had not been reported?” This keeps an unresolved laboratory finding from taking over the entire conversation.
Example 2: family testing can investigate uncertainty
Fictional teaching example. A child has a VUS in a gene relevant to the clinical investigation. The laboratory asks for parental samples. The parents worry that they are being offered a definitive test for the same disease.
The purpose may instead be to learn how the variant was inherited. The clinical team should explain what each possible family result would contribute. An inherited finding is not automatically benign; a newly arisen finding is not automatically pathogenic. Interpretation depends on the disease model and the rest of the evidence.
The ACMG/AMP sequence-variant guidelines place family evidence within a broader classification framework and state that a VUS should not be used for clinical decision-making. Evidence-gathering family studies are different from predictive testing based on an established disease-causing variant. Our trio-sequencing guide explains the distinction with inheritance examples.
Example 3: an online classification differs from the report
Fictional teaching example. A person searches the exact variant and finds both “uncertain significance” and “likely pathogenic” submissions in ClinVar. They assume that the most alarming label must be the correct one.
First confirm that the records refer to the same variant and relevant condition. Then examine the submitters, dates, evidence and review status. NCBI’s ClinVar documentation explains that stars represent the level of review supporting an assertion; they are not a numerical probability of pathogenicity.
Save the record link and ask the testing laboratory or genetics team whether it changes the interpretation. Our guide to conflicting ClinVar classifications walks through that process. A database disagreement is a reason to investigate the evidence, not to choose a diagnosis by counting labels.
How often does a VUS change classification?
There is no single percentage that predicts the future of every VUS. In Mersch and colleagues’ 2018 hereditary cancer study, 2,048 of 26,670 unique VUS were reclassified during the study’s follow-up, or 7.7%. Of those reclassified variants, 91.2% moved to benign or likely benign.
The denominator matters: that is 91.2% of the variants that changed, not 91.2% of all VUS. The study used one commercial laboratory’s historical testing cohort. Its results do not promise that a particular variant will be reclassified, tell us when that will happen, or provide an individual probability for a different setting.
Reclassification may also strengthen evidence for pathogenicity. Keep the original report so that an amended interpretation can be matched to the exact finding rather than to a remembered gene name.
What evidence could help?
The answer depends on why the variant remains uncertain. More population observations, informative family data or a suitable functional experiment may help in different cases. A research assay is useful only if its result can be interpreted for the relevant disease mechanism.
ClinGen’s functional-evidence recommendations describe why validation and appropriate controls matter. “Abnormal in the laboratory” does not by itself mean “causes this person’s disease.” Ask which specific evidence gap a proposed study addresses before investing in additional testing.
Leave the appointment with a follow-up plan
The ACMG guidance on reevaluation and reanalysis distinguishes reconsidering a reported variant from reanalyzing an entire case. Neither should be assumed to happen automatically on a fixed schedule.
- Keep the full report. Include the exact variant notation, classification, laboratory and date.
- Ask what remains unresolved. Is the gap the variant’s effect, the gene–disease relationship or its fit to the clinical picture?
- Clarify care now. What follows from established clinical information regardless of the VUS?
- Agree on contact. Who can request review, how are updates communicated and are there costs?
- Report meaningful changes. Ask how new diagnoses or relevant family information should reach the clinical team.
Our variant research worksheet can organize questions and source links. If the report remains uncertain, that does not make the symptoms less real. It means this finding has not yet provided a sufficiently supported explanation.