VUS in Genetics: What This Result Means for You

Genetic testing is a powerful tool for peering into your DNA to understand potential health risks. Sometimes, however, testing yields results that are not definitive, leaving you with more questions than answers. This guide explains one of the most common ambiguous results, a Variant of Uncertain Significance (VUS), and what this finding means for your health journey.

Defining a Variant of Uncertain Significance

Genetic testing laboratories analyze your genes for changes, known as variants, and compare them to a reference sequence of DNA. To determine the clinical relevance of any identified variant, scientists use a standardized five-tier classification system. This system categorizes a variant based on the strength of available evidence linking it to disease.

At either end of the spectrum are “Benign” and “Pathogenic” variants. A benign variant is a common genetic change that does not cause disease. A pathogenic variant is well-documented by scientific evidence to be a direct cause of a specific disease. Just inside these categories are “Likely Benign” and “Likely Pathogenic,” for which there is strong, but not yet definitive, evidence.

A Variant of Uncertain Significance sits directly in the middle of this classification system. A VUS result means a change has been found in your DNA, but at the time of testing, there is not enough scientific evidence to know whether it is a harmless variation or one that increases health risk. A VUS is not a diagnosis of a disease, nor does it confirm an elevated risk for developing one.

Think of your DNA as a complex recipe book for building and running your body. A VUS is like finding a typo in one of the recipes. The typo might be an insignificant error that doesn’t alter the final dish. Conversely, it could be a change that alters a step, leading to a different outcome. Without more information, you cannot know the effect of the typo.

Causes and Prevalence of VUS Results

The primary reason a VUS occurs is a lack of sufficient scientific data to confidently classify a genetic variant. Some genes are much more thoroughly studied than others. When a variant is identified that is very rare or has never been seen before, it often gets classified as a VUS by default until more evidence is gathered.

The likelihood of receiving a VUS result can also be influenced by your ancestry. Historically, genomic research and data collection has focused on individuals of European descent. This has created large gaps in the reference databases for populations from other parts of the world, such as those with African, Asian, or Hispanic ancestry.

Because more extensive genomic information is available for people of European ancestry, scientists have a better baseline for classifying variants in that population. For individuals of non-European ancestry, a normal, harmless variant might be flagged as a VUS simply because it has not been documented as frequently in scientific literature. This disparity means that VUS results are reported more often in underrepresented populations.

Medical Management with a VUS Finding

Receiving a VUS can feel unsettling, but this result should not be used to make clinical decisions. According to guidelines from the American College of Medical Genetics and Genomics (ACMG), medical management, such as decisions about cancer screenings or preventative surgeries, should not be altered based on a VUS. All clinical recommendations will be based on your personal and family medical history.

A genetic counselor plays an important part in this process. These professionals are trained to interpret complex genetic test results and put them into the context of your overall health profile. They will conduct a thorough assessment of your personal health history and the health of your close relatives to determine if there is a pattern of disease in your family that would warrant increased surveillance.

If you have a strong family history of a certain condition, like breast cancer, your medical team will recommend a screening plan based on that history, not the VUS. For this reason, testing other family members to see if they also carry the same VUS is not recommended. Since the significance of the variant is unknown, finding it in other relatives does not provide any actionable information and can cause unnecessary confusion.

Reclassification and Long-Term Outlook

The classification of a genetic variant is not permanent. As scientific research continues and more people undergo genetic testing worldwide, the collective pool of data on genetic variants grows. This expanding knowledge base allows laboratories to re-evaluate variants of uncertain significance periodically.

Over time, a VUS may be reclassified. This reclassification can go in either direction; new evidence might prove the variant is harmless, leading to a “Benign” classification. Alternatively, accumulating data could link the variant to disease risk, resulting in a reclassification to “Pathogenic.” Most VUS results that are eventually reclassified are downgraded to benign.

Genetics laboratories have internal procedures for reviewing new publications and data. Should the classification of your VUS change, the lab will issue an updated report to the clinician who ordered your test. This process can take several years, so it is beneficial to maintain a long-term relationship with your genetic counselor or healthcare provider. They will be your point of contact and will notify you if a new report becomes available.