Understanding a Variant of Uncertain Significance: What a VUS Means and Doesn't Mean

By Amanda Shrewsbury, MS, CGC

A VUS, or variant of uncertain significance, is one of the most confusing genetic testing results that someone can receive. The name itself signals ambiguity, without providing much guidance.

If you have received a VUS result, you may have read it as bad news, or you may not have known whether to worry at all. Neither reaction is quite right, and that is exactly why this result causes so much confusion. A VUS is not a clear answer, but it is also not the alarming finding it can feel like at first glance. Understanding what it actually represents can take a great deal of the worry out of it.

This post walks through what a VUS is, what it is not, why these results happen, what reclassification means, and what you should do if you have received one. Whether you are exploring testing, you have a VUS result in hand, or you have a family member who received one, this is for you.

What is a variant of uncertain significance?

A variant of uncertain significance (VUS) is a genetic change for which there is not yet enough scientific evidence to determine whether it affects health. The word variant simply means a difference in the DNA sequence compared with what is most common in the general population. Everyone carries many variants, and the vast majority are harmless differences that make us individuals. The question with any given variant is whether it is one of the harmless ones or one that affects health, and a VUS is a variant where that question does not yet have an answer.

In other words, a variant has been found, but the data available so far cannot tell us whether it is harmful or harmless.

To understand where a VUS sits, it helps to know that laboratories classify genetic variants along a five-category spectrum, established by the American College of Medical Genetics and Genomics (Richards et al., 2015):

  • Pathogenic — known to increase disease risk
  • Likely pathogenic — strong evidence of increased risk, though not yet definitive
  • Variant of uncertain significance (VUS) — not enough evidence to classify either way
  • Likely benign — strong evidence the variant is harmless
  • Benign — known to be harmless

A VUS sits squarely in the middle of this spectrum. It is the category that means, quite literally, "we do not know yet." It is not a finding that has been determined to be harmful, and it is not one that has been determined to be harmless. It is unresolved.

Is a VUS a positive result?

No. A VUS is not a positive result, and it should not be treated as one.

A positive result means a pathogenic or likely pathogenic variant has been identified, and that finding carries specific implications for screening, prevention, and sometimes treatment. A VUS carries no such implications, because its effect on health is unknown. This is one of the most important things to understand about a VUS: medical management is not based on a VUS alone. Decisions about screening, risk-reducing options, and prevention are guided by your personal and family history, not by the presence of an uncertain variant.

In practice, this means that having a VUS does not change your recommended cancer screening. If your personal and family history would warrant earlier or more intensive screening, that remains true regardless of the VUS. If it would not, the VUS does not add a reason for it.

Does a VUS mean I have cancer, or that I will get cancer?

No. A VUS does not tell you anything reliable about your cancer risk, because by definition its effect is unknown. It is not evidence that you carry a harmful variant, and it is not a prediction that you will develop cancer.

It is understandable to feel uneasy about a result that uses the word "variant" and appears on a hereditary cancer test. But a VUS is a flag for "this needs more study," not a signal of elevated risk. The uncertainty is about the science catching up to the variant, not about something concerning in your body.

How common are VUS results?

VUS results are common, not rare. The more genes a test examines, the higher the likelihood of finding at least one VUS, and modern multigene panels examine many genes at once. For many people who undergo panel testing, a VUS is a routine part of the result.

It is also important to understand that VUS results are not evenly distributed across all populations. People from ancestral backgrounds that have been historically underrepresented in genetic research are more likely to receive a VUS result, because the reference databases used to classify variants contain less data on genetic variation in those groups. One analysis of hereditary breast and ovarian cancer and Lynch syndrome genes found VUS rates of approximately 12.3 percent in people of African ancestry and 13.1 percent in people of Asian and Pacific Islander ancestry, compared with approximately 5.8 percent in people of European ancestry (Ndugga-Kabuye & Issaka, 2019).

This disparity is not a reflection of anything different about the health of these populations. It reflects a gap in the data, and it is one of the reasons the genetics field is working to expand the diversity of the people represented in research databases. As those databases grow, the disparity is expected to narrow.

Why do VUS results happen?

A VUS happens when a variant has been observed but not yet studied enough to know what it does. Every person carries many genetic variants, most of which are harmless individual differences. When a laboratory finds a variant that has not been well characterized, it cannot responsibly call it harmful or harmless without sufficient evidence, so it is classified as uncertain.

The evidence used to classify a variant comes from many sources, including how often the variant appears in the general population, whether it has been observed in families affected by disease, computational predictions of its effect, and laboratory studies of how it behaves. When these lines of evidence are incomplete or point in different directions, the variant remains a VUS until more information accumulates.

Will my VUS be reclassified, and how would I find out?

Most VUS results are eventually reclassified as the scientific evidence grows, and this is where the reassuring part of the story comes in. When reclassification happens, the large majority of VUS results are downgraded toward benign rather than upgraded toward pathogenic.

In a large study of hereditary cancer genetic testing, among the variants of uncertain significance that were reclassified, approximately 91 percent were downgraded to benign or likely benign, while approximately 9 percent were upgraded to pathogenic or likely pathogenic (Mersch et al., 2018). In other words, when a VUS is eventually resolved, it is far more likely to turn out to be harmless than harmful.

Reclassification is not immediate. The same study found that the median time to a downgraded report was a little over one year, and the median time to an upgraded report was closer to two years (Mersch et al., 2018). In practice, reclassification can take several years, and some variants remain uncertain for a long time before enough evidence accumulates.

When a variant is reclassified, the testing laboratory issues an amended report. This is why it is important to keep your contact information current with both the laboratory and your genetic counselor, so that any update reaches you. If you have moved or changed contact information since your test, it is worth making sure the lab and your provider have your current details.

Should my family members get tested for my VUS?

This question has two parts, and it is important to separate them.

First, regarding the VUS itself: testing relatives specifically for a VUS is generally not recommended. Because the variant's significance is unknown, testing a family member for it would not change their medical management, and a result would not provide clarity. There is a narrow exception, which is that a laboratory sometimes invites specific family members to undergo testing voluntarily to help with research and reclassification efforts. That kind of testing is different from clinical cascade testing and is entirely optional.

Second, and just as important: a VUS in the family does not cancel out a relative's own reasons to consider genetic testing. If a family member would be a good candidate for testing based on their own personal or family history, such as early-onset cancers, multiple affected relatives, or specific patterns of cancer in the family, they should pursue their own clinical genetic testing independent of the VUS. Their testing decision is driven by their own history, not by the uncertain variant. These are two separate questions: "should I be tested for this specific VUS?" (usually no) and "do I have my own reasons to consider genetic testing?" (possibly yes, and that stands on its own). Our guide to family history patterns that may indicate hereditary cancer risk can help you think through whether your own history warrants testing.

What should you do if you receive a VUS result?

The most useful approach to a VUS is to neither panic nor ignore it.

A few practical steps:

  • Talk with a genetic counselor. A genetic counselor can explain what your specific VUS means in the context of your personal and family history, and confirm that your screening recommendations are based on that history rather than on the variant.
  • Continue management based on your history. Your screening and prevention plan should follow your personal and family history. A VUS does not change it in either direction.
  • Keep your contact information current with the testing laboratory and your genetic counselor, so you are notified if your variant is reclassified.

A few other resources from our blog that may help:

The bottom line on uncertainty

Variants of uncertain significance, put simply, are pieces of information that science has not finished interpreting yet. The majority of VUS results are eventually reclassified as benign, while the minority are reclassified as pathogenic, and this process can take several years. In the meantime, your care continues to be guided by the things we do understand: your personal history and your family history.

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Talk with a ClearPath Genetic Counselor

If you have received a VUS result and want help understanding what it means for you, or you simply want to talk through your genetic testing options, we are here to help.

Have a Question? Text or call us at (720) 799-0730 or email us at hello@clearpathgenetics.com.

References

Mersch, J., Brown, N., Pirzadeh-Miller, S., Mundt, E., Cox, H. C., Brown, K., Aston, M., Esterling, L., Manley, S., & Ross, T. (2018). Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA, 320(12), 1266–1274.

Ndugga-Kabuye, M. K., & Issaka, R. B. (2019). Inequities in multi-gene hereditary cancer testing: Lower diagnostic yield and higher VUS rate in individuals who identify as Hispanic, African or Asian and Pacific Islander as compared to European. Familial Cancer, 18(4), 465–469.

Richards, S., Aziz, N., Bale, S., Bick, D., Das, S., Gastier-Foster, J., Grody, W. W., Hegde, M., Lyon, E., Spector, E., Voelkerding, K., & Rehm, H. L. (2015). Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine, 17(5), 405–423.

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This blog post is for educational purposes only and does not constitute medical advice, diagnosis, or treatment. Always seek the advice of your physician, genetic counselor, or other qualified healthcare provider with any questions you may have regarding a medical condition or your individual health needs.