Variants of uncertain significance (VUS)

A variant of uncertain significance, usually shortened to VUS, is a result of genetic testing. It means the laboratory found a difference in one of your genes but does not yet have enough evidence to say whether that difference matters.

The single most important thing to understand is this: a variant of uncertain significance is not a positive result. It does not mean a harmful gene change was found. It also does not mean one was ruled out. It is an incomplete answer rather than a middle one, and the difference between those two ideas matters enormously.

Many people hear “uncertain” and picture a result somewhere between normal and abnormal, as though it carried a moderate level of risk. That is not what it means. The variant is either harmless or harmful; the laboratory simply cannot yet tell which. For the great majority of people who receive this result, it eventually turns out to be harmless.

Receiving this result is frustrating, and studies have found that people who get a VUS often experience more worry than those told nothing was found at all. That reaction is understandable. This article explains what the result means, what happens to it over time, and what should and should not change because of it.

How genetic changes are classified

Every person carries millions of small differences in their DNA compared with the reference human genome. Almost all of them are harmless. When a laboratory sequences your genes, it finds many of these differences and must decide what each one means.

Laboratories use a five-step scale agreed internationally:

Pathogenic — Strong evidence the change stops the gene working. A positive result.
Likely pathogenic — Good but not conclusive evidence. Treated as a positive result in practice.
Variant of uncertain significance — Evidence is insufficient, conflicting, or absent. No conclusion can be drawn.
Likely benign — Good evidence the change is harmless.
Benign — Strong evidence the change is harmless. These are usually not reported at all.

A variant of uncertain significance sits in the middle of this scale, but it sits there for a reason that has nothing to do with the level of risk. It is a statement about the strength of the available evidence, not about the strength of the effect.

How often does this happen?

Far more often than most people expect. In one analysis of more than a million people who underwent hereditary cancer panel testing, roughly one in three had at least one variant of uncertain significance reported.

The main reason is that panels have grown. Testing that once examined one or two genes now routinely examines dozens. Every additional gene is another opportunity to find a difference nobody has characterized yet, so a larger panel finds more real answers and more uncertain ones at the same time.

Receiving this result is therefore common, and it is not a sign that anything went wrong with your test or that your case is unusual.

Why some variants cannot be classified

To decide whether a genetic change is harmful, a laboratory weighs several kinds of evidence:

How common the change is in the general population — A change carried by many healthy people is unlikely to cause a serious condition.
Whether it tracks with disease in families — If the change is consistently present in relatives who developed cancer and absent in those who did not, that is powerful evidence.
What it does to the protein in the laboratory — Experiments can test whether a specific change stops the gene’s protein from working.
What computer models predict — Useful as supporting evidence, but not sufficient on its own.
Whether the same change has been seen before — Laboratories share findings through international databases, so evidence accumulates across the world.

A variant remains uncertain when too few of these lines of evidence are available, most often because the change is rare and has been seen in only a handful of people.

People of non-European ancestry are more likely to receive uncertain results, not because their genomes are more prone to harm, but because reference databases and studies are mostly based on Europeans. A change known in one group may be unknown in another. This inequity is recognized, and efforts are underway to fix it. Recent research shows that once a variant is reclassified, outcomes and times are similar across groups.

What happens to a variant over time

A variant of uncertain significance is not a permanent verdict. Laboratories continue to gather evidence, and classifications are revisited as it accumulates. Two findings from large studies are worth knowing.

Most reclassified variants turn out to be harmless. In a study of variants in breast cancer genes, 92% of those that were reclassified were downgraded to benign or likely benign. Reclassification in the other direction, from uncertain to pathogenic, is much less common. Across genetic testing generally, movement toward less certainty is rare, accounting for well under 1% of all reclassifications.

It takes time. In the same study, about one in five variants had been reclassified over the study period, and the average time to reclassification was just under three years. Many variants remain uncertain for longer, and some may never be resolved.

Taken together: the most likely outcome is that your variant will eventually be reclassified as harmless, but that may take years, and in the meantime the honest position is that nobody knows.

What a VUS should not change

Because a variant of uncertain significance carries no established meaning, it should not by itself change your medical care. Specifically:

It should not be managed as a positive result. Screening schedules designed for people with a confirmed gene change do not apply on the basis of an uncertain one.
It is not a basis for risk-reducing surgery. Removing a healthy breast, ovary, stomach, or thyroid is a major irreversible decision, and an uncertain variant does not provide the evidence such a decision requires.
It should not usually change cancer treatment. Where a gene result determines eligibility for a particular drug, that eligibility generally rests on a confirmed pathogenic variant.
It should not be used to test relatives in the usual way. Testing family members for an uncertain variant does not tell them anything useful about their own risk, and it can create confusion. There is an important exception, described below.

This has not always been followed in practice. Surveys have found clinicians who would manage a patient with an uncertain variant the same way they would manage a patient with a confirmed one, and some studies have found higher rates of preventive mastectomy among women with uncertain results. Reassuringly, more recent and larger studies suggest practice has improved considerably, and that uncertain results are now less likely to drive treatment that guidelines do not support.

The practical implication is worth stating directly: if a decision about surgery or intensive screening is being made primarily because of an uncertain variant, it is entirely reasonable to ask whether that decision would be the same without it, and to ask for input from a genetics service.

What guides your care instead

With the variant set aside, decisions rest on the same things they would have rested on if the test had found nothing at all:

Your personal history — Whether you have had cancer, at what age, and of what type.
Your family history — Who in your family has had cancer, how closely related they are, which side of the family, the specific type, and the age at diagnosis. For many people, this remains the strongest information available.
Risk calculation tools — Which combine these factors into an estimate that can guide whether additional screening is appropriate.
Other findings on the same test — A panel may have found nothing else, or it may have found something that does have established meaning.

This is an important point for people whose families have a striking history of cancer. An uncertain result does not explain that history, and it does not mean enhanced screening should stop. Where family history alone warrants closer follow-up, that follow-up continues.

What it means for your family

Because an uncertain variant has no established meaning, it generally has no implications for relatives, and routine testing of family members is not recommended. A relative who tested positive for the same uncertain variant would learn nothing useful, and one who tested negative would gain no reassurance.

There is one meaningful exception. A genetics service may sometimes arrange testing of specific relatives as part of a family study, designed to work out whether the variant tracks with cancer in your family. If the variant is consistently present in relatives who developed cancer and absent in those who did not, that contributes real evidence toward classifying it. This is quite different from testing relatives to tell them their own risk, and it is coordinated by the genetics team rather than requested independently.

What relatives can act on in the meantime is the family history itself. Whether or not a gene change is ever identified, a family history of cancer may be reason enough for earlier or more frequent screening, and that conversation does not need to wait for the variant to be resolved.

What you can do

An uncertain result is unsatisfying, but there are a few things that genuinely help.

Ask how you will be told if the classification changes. Practice varies. Some laboratories notify the ordering clinician automatically; others do not, and the responsibility for checking may sit with the clinic or with you. This is worth clarifying rather than assuming.
Stay connected to the genetics service. Reconnecting every year or two is reasonable, and is often the most reliable way to learn about a reclassification.
Keep a copy of the report. It names the exact variant, which is what any future clinician or laboratory will need. Keeping it with your own records makes this much easier years later.
Keep your family history up to date. Since your care is being guided by family history rather than by the variant, new cancers in the family are relevant information and worth reporting.
Ask whether a family study would be useful. This is not offered in every case, but where a family is informative it can help resolve the question.

It is also reasonable to say that the uncertainty itself is difficult. Being told that something was found but nobody knows what it means sits awkwardly between reassurance and alarm. Genetics services are used to this conversation, and asking for a follow-up appointment simply to talk it through is a legitimate use of their time.

Questions to ask your doctor

Which gene is the variant in, and what condition is that gene associated with?
Does this result change anything about my screening or treatment?
If a decision about surgery is being considered, would that decision be the same without this result?
What does my personal and family history alone suggest about my risk?
Should I still have enhanced screening based on my family history?
How will I be told if the variant is reclassified, and whose responsibility is it to check?
How often should I reconnect with the genetics service?
Would testing other family members help classify this variant?
Should my relatives be tested for this variant, or is that not useful?
Were any other findings on my panel that do have established meaning?
Could my ancestry be a reason this variant has not been classified?
Can I see a genetic counselor to talk this through?