When receiving results from genetic or molecular diagnostic testing, the designation of “Uncertain Clinical Significance” can be confusing and anxiety-provoking. This result indicates that a change, or variant, was found in a person’s genetic code, but current medical science cannot definitively determine whether that change causes disease or is simply a harmless variation. The finding leaves patients and their healthcare providers in a complex gray area, unable to make clear decisions about diagnosis, prognosis, or treatment based solely on the test result. Understanding this uncertainty is the first step in managing a result that carries significant ambiguity.
Defining Uncertain Clinical Significance
A finding of Uncertain Clinical Significance (UCS), often referred to as a Variant of Uncertain Significance (VUS), means the laboratory identified a change in the DNA sequence that lacks sufficient evidence for classification. This uncertainty reflects the current state of medical knowledge about that specific variant, not a flawed test. Laboratories use established guidelines to evaluate variants, but when data is insufficient or contradictory, the variant is placed into this neutral category. The VUS designation is temporary, signifying that the variant is neither confirmed as pathogenic (disease-causing) nor benign (harmless), and requires more research before a definitive classification can be made.
Why Results Remain Ambiguous
The primary reason a variant is labeled UCS is a lack of published data or clinical observations for that specific genetic change. Many variants are extremely rare, meaning they have not been seen frequently enough in the population for researchers to establish a clear pattern of association with a disease. Without multiple examples across different patients and families, the variant’s effect on gene function remains unknown.
Another factor is the complexity of the specific gene or marker in which the variant is located. A variant may occur in a region of a gene whose biological function is poorly understood, making it difficult to predict whether the change disrupts the gene’s intended purpose. Additionally, the majority of genomic data available today comes from individuals of European ancestry, leading to an increased number of VUS findings for individuals from other ethnic backgrounds due to limited population studies.
Sometimes, a variant may have conflicting lines of evidence, where some data suggests it might be harmful, while other data, such as its presence in healthy individuals, suggests it is benign. When evidence is mixed, or when computational prediction algorithms disagree on the variant’s impact, the necessary threshold of certainty is not met, and the laboratory must report it as a VUS. This gap between finding a variant and understanding its biological effect is common because genomic technology advances faster than the scientific ability to interpret all the resulting data.
Placing the Variant on the Spectrum of Results
Genetic testing results are typically sorted into a five-tier classification system based on the variant’s likelihood of causing disease. At the two ends of this spectrum are “Pathogenic” and “Benign” classifications, which provide the clearest guidance for clinical decisions. A Pathogenic result means the variant is known to cause disease with greater than 99% certainty, while a Benign result means it is considered harmless.
The classification system also includes “Likely Pathogenic” and “Likely Benign” categories, assigned when there is strong evidence, but not absolute proof, for either disease causation or harmlessness. For example, a Likely Pathogenic variant has an estimated 90-99% probability of being disease-causing. These categories provide a high degree of confidence for clinical decision-making.
The Variant of Uncertain Significance (VUS) occupies the middle position on this five-tier scale, representing the true gray area. This classification is applied when the available evidence does not meet the criteria for Likely Benign or Likely Pathogenic, leaving the probability of disease causation in the middle range. A VUS requires careful interpretation and should not be used to guide medical treatment until more information is gathered.
Practical Guidance and Reclassification
Upon receiving a VUS result, the immediate next step often involves meeting with a genetic counselor, who is trained to explain the complexities of the finding and manage the uncertainty. The counselor provides context by reviewing the patient’s personal medical history and family history to determine if the VUS aligns with any observed health patterns. The medical recommendation is usually to proceed with clinical management based on the patient’s symptoms and family history, rather than on the VUS itself.
In some cases, a process known as cascade testing may be recommended to help resolve the uncertainty. This involves testing other family members, both those with and without the related medical condition, to see if the variant travels, or “segregates,” with the disease. If the VUS is found only in family members who have the condition, it provides strong evidence that the variant is likely pathogenic and can lead to reclassification.
A VUS is a dynamic, temporary classification that is subject to change as scientific knowledge evolves. Laboratories continuously gather new data from global databases, scientific publications, and functional studies. This ongoing process is called reclassification, meaning a VUS may eventually be “upgraded” to pathogenic or, more commonly, “downgraded” to benign. Patients should maintain contact with their healthcare provider to ensure they receive updated reports, as a reclassification can significantly impact future medical care.