What is a VUS (Variant of Uncertain Significance) in BRCA?

Getting genetic test results can be an anxious experience, especially if you see the words “Variant of Uncertain Significance” (VUS) on your report. A VUS simply means that the laboratory found a change in your BRCA1 or BRCA2 gene, but they do not yet have enough scientific evidence to know if this change increases your risk of cancer, or if it is just a normal, harmless variation in your DNA ^[1].

How is a VUS Managed Clinically?

When a genetic test returns a VUS, the result is inconclusive. However, major medical guidelines advise doctors to manage your care as if the result were negative ^[2][3]. Because the risk is unproven, doctors do not use a VUS to guide your cancer prevention plan ^[2]. This means that major, irreversible medical decisions—such as preventative surgeries (mastectomy or oophorectomy)—should never be made based solely on a VUS result ^[2].

Additionally, if you have already been diagnosed with cancer, a VUS is generally not used to make active treatment decisions, such as determining if you qualify for precision therapies like PARP inhibitors ^[4].

Instead, your cancer screening, prevention, and treatment plans will be based entirely on your personal medical history and your family’s history of cancer ^[3][5]. If your family history suggests a high risk of cancer, you may still be advised to undergo extra screening (such as breast MRIs), but this recommendation would be due to your family tree, not the VUS result ^[3]. Furthermore, because the variant’s risk is unknown, testing family members (like children or siblings) for the VUS is usually not recommended unless it is part of a research study to help clarify the variant’s meaning.

Will My VUS Ever Be Clarified?

Yes, it is very common for a VUS to be reclassified as researchers gather more genetic data from families around the world ^[4]. Over time, genetic laboratories update their databases and can often definitively determine whether a variant is harmful (pathogenic) or harmless (benign).

Here is what research shows about how these variants change over time:

• Many variants are eventually reclassified: In one large study, about 25% of VUS results were eventually reclassified as more information became available ^[6].
• Most are harmless: When a VUS is reclassified, the vast majority—over 90%—are downgraded to “benign” or “likely benign,” meaning they do not cause an increased risk of cancer ^[6]. Only about 9% of reclassified variants are upgraded to pathogenic ^[6].

Waiting in “limbo” for a variant to be reclassified can be emotionally frustrating. Because it can take months or even years for a laboratory to reclassify a VUS ^[6], it is important to stay in touch with your genetic counselor or doctor ^[4]. Many labs will automatically notify the medical provider who ordered the test if your variant’s status ever changes.

However, because doctors sometimes retire or you might change clinics, it is a good idea to take ownership of your follow-up. Always ask for a physical or digital copy of your genetic test report. Keeping this report ensures you always have the name of the testing laboratory and the exact code for your variant. You can also ask your care team how often you should check back for updates, such as during an annual check-in.