Variant of Uncertain Significance: What It Means

You underwent genetic testing and your results include something called a variant of uncertain significance, or VUS. This can be one of the more confusing outcomes to receive. Here is what you need to know: a VUS is not a reason to panic, and it is not a reason to take clinical action.

Your DNA contains approximately 20,000 genes, and natural variation between individuals is normal. A VUS falls between clearly pathogenic (disease-causing) and clearly benign (harmless). The laboratory found a change in your DNA, but there is not yet enough evidence to determine whether that change increases cancer risk or is simply a benign variation. VUS findings can occur in well-studied genes like BRCA1 and BRCA2 as well as in less-studied genes.

Up to 20 to 40 percent of individuals who undergo multi-gene panel testing will have at least one VUS reported. VUS rates are also higher in individuals from populations that are underrepresented in genetic research databases. As research diversifies, reclassification rates are expected to improve. For more on what panel testing involves, see our BRCA and hereditary cancer testing guide.

Do not use it to make medical decisions. A VUS should not lead to changes in screening, surgical planning, or medication. Clinical management should be guided by your personal and family history, not by the VUS. For guidance on all result types, see understanding your genetic test results.

• Continue your current screening plan.
• Keep your genetic test report.
• Stay in contact with your genetic counselor or testing laboratory. Many laboratories proactively notify patients when a VUS is reclassified.

As more individuals are tested and more functional studies are conducted, many VUS are reclassified. The majority are eventually reclassified as benign. Roughly 7 to 10 percent of VUS are reclassified within five years of the initial report. Learn about the specific genes tested in our BRCA genes guide.

Receiving a VUS can feel like being left in limbo. It may help to remember that a VUS is, in practice, much more likely to be benign than pathogenic. A genetic counselor can help put the finding in context. For broader information about genetic counseling for hereditary cancer, see our pillar guide. Learn about the testing process and counselor support.

One of the most common questions after receiving a VUS result is whether family members should also be tested. The short answer: generally, no — not for the VUS itself.

Unlike a pathogenic variant, a VUS does not have established clinical significance. Testing family members for an uncertain variant can create confusion and anxiety without providing actionable information. In most cases, genetic counselors recommend against cascade testing for a VUS.

There are limited exceptions. In some cases, a laboratory may request family testing (called segregation analysis) to help determine whether the VUS tracks with disease in the family. This is a research-oriented approach, and your genetic counselor will advise you if it applies to your situation.

If your family has a strong history of cancer regardless of your VUS, relatives may still benefit from their own independent genetic evaluation based on family history criteria. This is different from cascade testing for a specific variant. You can learn more about who qualifies for hereditary cancer evaluation in our hereditary cancer screening guide.

Not all healthcare providers are equally familiar with VUS results, and miscommunication can lead to inappropriate clinical decisions. Here are practical tips for discussing your VUS with your medical team:

• Bring your genetic test report. The full laboratory report provides the variant classification and any relevant context. Do not rely on a summary alone.
• Clarify that a VUS is not a positive result. Some providers may conflate VUS with pathogenic findings. If your provider recommends changes to your screening or treatment based on a VUS, ask for the rationale and consider a second opinion from a genetic counselor.
• Ask about periodic reassessment. Request that your provider or genetic counselor periodically check whether your VUS has been reclassified. Some laboratories offer automated notification services.
• Discuss your family history separately. Your screening plan should be based on your personal and family history, not on the VUS. Make sure your provider is evaluating your risk holistically.