Genomic testing is a valuable tool in modern medicine, offering a detailed look into an individual’s DNA. While many results provide clear answers, a significant number of people receive a Variant of Uncertain Significance (VUS). This ambiguous finding can be stressful, causing confusion and anxiety about health and future medical management. Communicating the inherent ambiguity of a VUS is a necessary part of the genetic testing process.
Layman’s Definition of a VUS Result
A VUS is a detected change in your DNA sequence that scientists cannot yet definitively classify as either harmless or disease-causing. Think of your DNA as a massive instruction manual for your body; a VUS is essentially a typo discovered in that manual. The laboratory knows a letter has been changed, but they do not know if that change matters.
Genetic testing results fall into three main categories: Pathogenic, Benign, and the VUS, which represents a gray area. A pathogenic variant is a confirmed change that leads to disease, while a benign variant is a common, normal variation with no impact on function.
The VUS classification means there is insufficient or conflicting evidence to place the variant into either clear category. It is not a diagnosis of disease, but rather an acknowledgment of scientific uncertainty. This classification indicates the probability of the variant being disease-causing is somewhere between 10% and 90%.
Why Genetic Testing Results Remain Undefined
The uncertainty surrounding a VUS reflects the limits of current scientific knowledge, not a flaw in the testing process. One primary reason for a VUS classification is the rarity of the variant in the general population. If a specific variant has only been seen a few times, there is not enough population data to establish a clear link to a health condition.
Another contributing factor is the lack of functional studies for many variants. Specialized laboratory research is often needed to confirm whether a DNA change affects the function of the corresponding protein. Without this experimental evidence, variants cannot be conclusively labeled as pathogenic.
Insufficient family data also prevents a clear classification. Geneticists often look for a clear pattern of inheritance, called segregation, where the variant is present in affected family members and absent in unaffected ones. If the disease onset is late in life, or if family members are unavailable for testing, this crucial evidence is missing.
Immediate Clinical Implications of a VUS
The most important takeaway for a patient is that a VUS result typically does not change current medical surveillance or treatment plans. Medical guidelines recommend that VUS results should not be used to guide medical decision-making. Management decisions must continue to be based on a patient’s personal and family medical history, along with other clinical factors.
For a patient undergoing genetic testing, receiving a VUS means the cause of the disease has not been identified by the test. This result should not prompt drastic actions like unnecessary surgery or excessive cancer screenings. Such interventions carry risks and are only recommended for confirmed pathogenic variants.
The VUS should generally not be used for predictive testing of other family members. Testing healthy relatives for an uncertain result provides no actionable information and can introduce anxiety and ambiguity. Until the variant is reclassified, the result remains uninformative for clinical care.
The Reclassification Process and Ongoing Monitoring
A VUS classification is not permanent; it is a temporary holding category subject to change as new information emerges. The process of reclassification is driven by the continuous accumulation of evidence from research and clinical data. Laboratories regularly review VUS results, often at set intervals or when new data becomes available in public databases.
The primary force behind reclassification is the growth of shared databases, such as ClinVar, where laboratories worldwide submit variant data. As more people undergo testing and more functional studies are published, the evidence required to move a VUS to a definitive category accumulates. A significant number of variants are re-evaluated within a few years of initial reporting.
Patients must maintain up-to-date contact information with the ordering provider and the laboratory, as they will notify the patient if the VUS is reclassified. While reclassification can move a VUS to either a pathogenic or benign category, the vast majority of VUS results—often over 90% in hereditary cancer testing—are eventually reclassified as benign or likely benign. This statistic offers a realistic perspective on the likely future outcome of an uncertain result.