What is a variant of uncertain significance (VUS) in a genetic test?
A VUS is a result with an open question attached, and its label can change as evidence builds. Whether the report came from a consumer test or a clinical lab matters too.
Arun Verma, co-founder of Triangle · 2026-10-17
This is not clinical evidence and not medical advice. It does not replace your care team. Discuss anything here with your clinician before you act on it.
What is a variant of uncertain significance (VUS)?
It's a change in DNA that a test found, where it is unclear whether the change is connected to a health condition. In many cases the variant is so rare in the population that little information is available about it, NHGRI's glossary says, and more information is typically needed to tell whether it is disease related. Other names for it include variant of unknown significance and unclassified variant, so your report may word it differently. Most gene variants have no impact on health or development, MedlinePlus says. That is true of variants in general; a VUS is one that has not been confirmed either way.
Where does a VUS fall among the usual result categories?
In the middle. Labs often score variants on a five-point scale: pathogenic, likely pathogenic, uncertain significance, likely benign and benign. MedlinePlus describes the middle group as variants that cannot be confirmed to play a role in disease, because there may not be enough research to confirm or refute a link or the research may conflict. Being linked to a disease doesn't make every variant in a gene pathogenic. Which categories appear on a report depends on the lab. According to a toolkit for non-genetics clinicians from the NIH-funded CSER Consortium, hosted by NHGRI, some laboratories report only pathogenic and likely pathogenic variants while others include variants of uncertain significance, and laboratories typically leave out benign and likely benign findings. You could ask the lab or a genetic counselor which categories its reports include.
Does a VUS confirm a condition or a higher risk?
No. A VUS cannot confirm or rule out a specific diagnosis, and it cannot indicate whether a person has an increased risk of developing a disorder, according to MedlinePlus. Clinicians are advised not to use a VUS for clinical decision-making until it is reclassified, as a toolkit for non-genetics clinicians from the NIH-funded CSER Consortium, hosted by NHGRI, puts it.
Why does a variant end up a VUS, and how common is it?
Several things can lead to the label. The effect of the DNA change on how the gene works may not be known, there may be too little genetic data to link it to a disease, or the person may have no symptoms, or different symptoms than expected for that variant. How common it is depends on the test. A toolkit for non-genetics clinicians from the NIH-funded CSER Consortium, hosted by NHGRI, says a VUS is common among large tests such as gene panels, exome sequencing and genome sequencing. As of 2020, it adds, some studies report a VUS in as many as 1 in 3 patients. NHGRI's glossary narration says that at present there is much more extensive genomic information about people of European ancestry than any other group, leading to many more VUS in those other groups.
Why can a VUS be reclassified over time?
Because the evidence behind it can grow. As more data accumulate over time, a VUS may be reclassified as likely pathogenic or likely benign, according to a toolkit for non-genetics clinicians from the NIH-funded CSER Consortium, hosted by NHGRI. NHGRI's glossary says the information that may help includes more extensive population data, functional studies, and tracing the variant in family members who do or don't have the same health condition. MedlinePlus adds that variants should be re-evaluated periodically. Reclassification may come years after the original test. As of 2020, the toolkit says, many clinical labs will, as a matter of policy, issue an amended report when a VUS is reclassified to a category considered clinically actionable, usually sent to the physician who ordered the test. For consumer tests, companies may provide updates to results, sometimes for a fee, MedlinePlus says, so you could ask a company whether and how it sends them.
Can two labs label the same variant differently?
It can happen, and ClinVar, a public database, is built to show where submitters agree and where they differ. ClinVar says the classification on each submitted record comes only from the submitter, and its staff do not curate it. When submitters land at different levels, for example an uncertain term and a benign term, the combined entry shows 'Conflicting classifications of pathogenicity'. Each submission lists the submitter's name and the dates first submitted and updated, and earlier versions are kept when a submitter updates a record.
How is a VUS on a consumer DNA report different from one on a clinical report?
The two reports are held to different standards. MedlinePlus says direct-to-consumer tests are often for information only and generally not meant to diagnose, prevent or treat a health condition, and that their results typically need confirming with testing ordered through a healthcare provider before they count as diagnostic. Results from provider-ordered clinical testing can be used to diagnose specific conditions or guide care. For a variant found on a consumer test, a clinician FAQ hosted by NHGRI, from the ISCC-PEG group, says it may or may not be clinically actionable, because the standards and guidelines for interpreting it differ from those of clinical genetic testing. The FAQ also says raw data from a consumer test is uninterpreted genotype information. You could ask whether the lab behind a report has CLIA, CAP or AABB certification, a question MedlinePlus lists for consumer companies.
What could I ask the lab or a genetic counselor about a VUS?
A few fair questions: which categories the lab uses and where this variant sits, what evidence put it there, what would be needed to reclassify it, whether the lab reanalyzes variants and sends amended reports, and who would receive one. For a consumer report, MedlinePlus lists questions to consider about the company, such as whether it discusses the need for confirming tests, whether genetic counselors are on staff, and whether you would be notified if future research changes your results. You could ask whether referral to genetic services or a periodic check-in with the testing lab makes sense; a toolkit for non-genetics clinicians from the NIH-funded CSER Consortium, hosted by NHGRI, lists both among next steps for clinicians. Providers consider medical history, family history and the type of test when interpreting results, so another question is which of those your provider or counselor took into account.
Sources
- NHGRI Talking Glossary: Variant of Uncertain Significance (VUS): NHGRI's glossary says that when analysis of a patient's genome identifies a variant but it is unclear whether the variant is connected to a health condition, the finding is called a variant of uncertain significance (VUS).
- NHGRI Talking Glossary: Variant of Uncertain Significance (VUS): NHGRI's glossary says that in many cases these variants are so rare in the population that little information is available about them, and that typically more information is required to determine whether the variant is disease related.
- Guide to Interpreting Genomic Reports: A Genomics Toolkit (CSER Consortium Practitioner Education Working Group, April 2020; hosted by NHGRI), printed p. 33: The CSER Consortium toolkit's glossary defines a variant of uncertain significance as a change in the DNA sequence whose association with disease is unknown, and says it is also called a variant of unknown significance, unclassified variant, or sometimes simply a VUS.
- MedlinePlus Genetics: Do all gene variants affect health and development?: MedlinePlus says only a small percentage of variants cause genetic disorders and that most have no impact on health or development.
- MedlinePlus Genetics: Do all gene variants affect health and development?: MedlinePlus defines a VUS as a variant that cannot be confirmed to play a role in the development of disease, because there may not be enough scientific research to confirm or refute a disease association or the research may be conflicting.
- MedlinePlus Genetics: Do all gene variants affect health and development?: MedlinePlus says gene variants, as they relate to genetic disorders, are classified into one of five groups: pathogenic, likely pathogenic, variant of uncertain significance, likely benign and benign.
- MedlinePlus Genetics: Do all gene variants affect health and development?: MedlinePlus says that just because a gene is associated with a disease does not mean that all variants in that gene are pathogenic.
- Guide to Interpreting Genomic Reports: A Genomics Toolkit (CSER Consortium Practitioner Education Working Group, April 2020; hosted by NHGRI), printed p. 5: The CSER Consortium toolkit says laboratories often use a 5-point scale from benign to pathogenic, with likely benign, variant of uncertain significance and likely pathogenic in between.
- Guide to Interpreting Genomic Reports: A Genomics Toolkit (CSER Consortium Practitioner Education Working Group, April 2020; hosted by NHGRI), printed p. 5: The CSER Consortium toolkit says laboratories vary in the types of variants they report: some may report only pathogenic and likely pathogenic variants while others also report variants of uncertain significance, and laboratories typically do not report benign or likely benign findings.
- MedlinePlus Genetics: What do the results of genetic tests mean?: MedlinePlus says an uninformative result such as a VUS cannot confirm or rule out a specific diagnosis and cannot indicate whether a person has an increased risk of developing a disorder.
- Guide to Interpreting Genomic Reports: A Genomics Toolkit (CSER Consortium Practitioner Education Working Group, April 2020; hosted by NHGRI), printed p. 10: The CSER Consortium toolkit says that until a VUS is reclassified, clinicians are advised not to use a VUS result for clinical decision-making.
- Guide to Interpreting Genomic Reports: A Genomics Toolkit (CSER Consortium Practitioner Education Working Group, April 2020; hosted by NHGRI), printed p. 10: The CSER Consortium toolkit lists reasons a variant is classified as a VUS: the effect of the genetic alteration on gene function is not known; there are insufficient genetic data to confirm an association with risk of the disease; or the patient is unaffected or has different symptoms than expected based on the variant found.
- Guide to Interpreting Genomic Reports: A Genomics Toolkit (CSER Consortium Practitioner Education Working Group, April 2020; hosted by NHGRI), printed p. 11: The CSER Consortium toolkit (2020) says finding a VUS is common among large-scale tests such as gene panels, whole exome and whole genome sequencing, and that some studies report a VUS in as many as 1 in 3 patients (the toolkit's footnote for that figure is a 2013 journal paper).
- NHGRI Talking Glossary: Variant of Uncertain Significance (VUS): NHGRI's glossary narration (Teri Manolio, M.D., Ph.D., Director, Division of Genomic Medicine, NHGRI) says that at present there is much more extensive genomic information about people of European ancestry than any other group, leading to many more VUS in those other groups.
- Guide to Interpreting Genomic Reports: A Genomics Toolkit (CSER Consortium Practitioner Education Working Group, April 2020; hosted by NHGRI), printed p. 10: The CSER Consortium toolkit says that as more data accumulate over time, a VUS may be reclassified to likely pathogenic or likely benign.
- NHGRI Talking Glossary: Variant of Uncertain Significance (VUS): NHGRI's glossary says the information that may help determine whether a variant is disease related may include more extensive population data, functional studies, and tracing the variant in other family members who have or do not have the same health condition.
- MedlinePlus Genetics: Do all gene variants affect health and development?: MedlinePlus says it is important to re-evaluate variants periodically and that the classification of a variant can change over time as more information about the effects of variants becomes known through additional scientific research.
- Guide to Interpreting Genomic Reports: A Genomics Toolkit (CSER Consortium Practitioner Education Working Group, April 2020; hosted by NHGRI), printed p. 11: The CSER Consortium toolkit (2020) says reclassification of a VUS may occur years after the original test was performed, and that many clinical genetic testing laboratories will, as a matter of policy, issue an amended report when a VUS is reclassified to a category considered clinically actionable, usually sent to the physician who ordered the test.
- MedlinePlus Genetics: What do the results of direct-to-consumer genetic testing mean?: MedlinePlus says direct-to-consumer genetic testing companies may provide updates (sometimes for a fee) to a person's results as research and technology improves.
- NCBI ClinVar: Representation of classifications in ClinVar (last updated 2025-08-15): ClinVar's classification page says the classification on a submitted record is provided only by the submitter and that ClinVar staff do not curate submitted classifications.
- NCBI ClinVar: Representation of classifications in ClinVar (last updated 2025-08-15): ClinVar's classification page says that when aggregating submissions it reports conflicts between levels of pathogenicity (any pathogenic/risk term versus any uncertain term, pathogenic/risk versus benign, and uncertain versus benign) as 'Conflicting classifications of pathogenicity', while Benign and Likely benign from different submitters appear as 'Benign/Likely benign' rather than as a conflict.
- NCBI ClinVar: About ClinVar (last updated 2026-04-29): ClinVar's About page says it accepts submissions from multiple groups so as to reflect both consensus and conflicting assertions of clinical significance.
- NCBI ClinVar: About ClinVar (last updated 2026-04-29): ClinVar's About page lists the submitter's name and the dates first submitted and updated among the data elements shown for a submission, and says that when submitters update their records the previous version is retained for review.
- MedlinePlus Genetics: What do the results of direct-to-consumer genetic testing mean?: MedlinePlus says direct-to-consumer tests are often for information purposes only and generally not meant to diagnose, prevent or treat a disease or health condition, and that their standards and guidelines differ from those for clinical genetic testing.
- MedlinePlus Genetics: What should I know before proceeding with direct-to-consumer genetic testing?: MedlinePlus says direct-to-consumer test results typically need to be confirmed by additional testing ordered through a healthcare provider before they can be considered diagnostic and used to make medical decisions.
- MedlinePlus Genetics: What is direct-to-consumer genetic testing?: MedlinePlus says genetic testing ordered through a healthcare provider is called clinical genetic testing, and that its results can be used to diagnose specific medical conditions or guide decisions about a person's care.
- ISCC-PEG DTC-GT Project Group: Direct-to-Consumer Genetic Testing FAQ for Healthcare Professionals (hosted by NHGRI; last updated June 14, 2023): The ISCC-PEG DTC-GT Project Group's FAQ for healthcare professionals says that when a variant is found by direct-to-consumer testing, it may or may not be clinically actionable because the standards and guidelines for interpreting the variant are different from those of clinical genetic testing.
- ISCC-PEG DTC-GT Project Group: Direct-to-Consumer Genetic Testing FAQ for Healthcare Professionals (hosted by NHGRI; last updated June 14, 2023): The ISCC-PEG DTC-GT Project Group's FAQ for healthcare professionals says raw data from a direct-to-consumer test is uninterpreted genotype information.
- MedlinePlus Genetics: What should I know before proceeding with direct-to-consumer genetic testing?: MedlinePlus lists, among questions to consider about a direct-to-consumer company, whether the laboratory has a certification from CLIA, the College of American Pathologists (CAP) or AABB.
- MedlinePlus Genetics: What should I know before proceeding with direct-to-consumer genetic testing?: MedlinePlus lists questions to consider about a direct-to-consumer company, including whether it discusses the need for additional testing to confirm results, whether it has genetics professionals such as genetic counselors on staff, and whether you will be notified if future research changes or impacts your results.
- Guide to Interpreting Genomic Reports: A Genomics Toolkit (CSER Consortium Practitioner Education Working Group, April 2020; hosted by NHGRI), printed p. 12: The CSER Consortium toolkit lists, among next steps to consider for a VUS, referral to genetic services (a medical geneticist and/or genetic counselor) and contacting the testing laboratory periodically for reanalysis of the variant to see whether more is known about its disease association.
- MedlinePlus Genetics: What do the results of genetic tests mean?: MedlinePlus says that when interpreting test results, health care providers consider a person's medical history, family history and the type of genetic test that was done.
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