Genetic testing offers insights into an individual’s risk for various health conditions by analyzing a person’s DNA for changes, known as variants. While some test results provide clear answers, others can introduce uncertainty. One of the most common sources of this ambiguity is the identification of a Variant of Unknown Significance, or VUS.
A VUS result means a change has been found in a person’s DNA, but scientists do not yet have enough information to determine if it is harmful or harmless. It represents a gap in current scientific knowledge rather than a definitive statement about a person’s health. This outcome is a regular part of genetic analysis as testing becomes more comprehensive.
Understanding Genetic Variants: Beyond Simple Good or Bad
Every individual’s genetic code contains thousands of variations, which are responsible for human diversity. Most of these variants have no impact on health, but some can affect how a gene functions, potentially increasing the risk for certain medical conditions. To standardize the interpretation of these findings, scientists use a five-tier classification system to categorize variants based on the evidence linking them to disease.
The categories range from “Benign” and “Likely Benign” for harmless variants, to “Pathogenic” and “Likely Pathogenic” for variants with strong evidence of being disease-causing. These classifications help clinicians understand the implications of a genetic finding. A pathogenic variant, for instance, can confirm a diagnosis or indicate a high risk for developing a specific condition.
Positioned in the middle of this spectrum is the “Variant of Unknown Significance.” A VUS is assigned when the available evidence is insufficient or conflicting, preventing scientists from placing it in either the benign or pathogenic categories. It is a declaration of uncertainty that highlights the evolving nature of genetic research.
The Challenge of “Unknown Significance” in Genetic Variants
The classification of a genetic variant as being of “unknown significance” arises from several scientific challenges. Interpreting the human genome is an intricate process, and a VUS designation reflects an information gap. The main reasons for this uncertainty include:
- The rarity of the variant. If a genetic change has been seen in only a few people, there is not a large enough data pool to establish a pattern of association with a health condition.
- A lack of extensive genomic data on non-European populations, which can lead to a higher rate of VUS results in these groups.
- The absence of functional studies. Scientists may not know what a specific change does to the protein a gene produces without time-consuming laboratory research.
- Conflicting evidence, where some data or computational models suggest a harmful effect while other information suggests a benign one.
Navigating a VUS Result: Patient Implications and Clinical Approaches
Receiving a VUS result can be a source of anxiety for patients and their families. The uncertainty of the finding can be difficult to process, leaving individuals with more questions than answers about their health. This emotional response is a recognized part of the genetic testing experience.
A VUS result does not trigger immediate changes to a person’s medical management. Clinical decisions are based on firm evidence, and since a VUS is not a definitive finding, it is not used to recommend preventative surgeries or alter screening schedules. Instead, medical recommendations will continue to be based on the individual’s personal and family medical history.
A genetic counselor can help individuals understand the complexities and limitations of their test results. They can explain what a VUS means, address emotional concerns, and outline the next steps. One potential step is segregation analysis, where other family members are tested to see if the VUS is present in relatives who have the health condition and absent in those who do not.
Shedding Light on VUS: The Process of Reclassification
A VUS classification is not permanent. These findings are often re-evaluated over time as new scientific evidence becomes available through a process known as reclassification. This is a primary reason why maintaining contact with a genetics clinic is recommended after receiving a VUS result.
The reclassification of a VUS is driven by the global accumulation of new data from researchers and laboratories in large, public databases like ClinVar. As more people undergo genetic testing, a rare variant may be identified in more individuals, allowing scientists to observe whether it tracks with a disease. New laboratory studies might also reveal how a variant affects a gene’s function, providing evidence for its re-evaluation.
This new information allows laboratories to periodically review their VUS classifications. A VUS may be downgraded to “Benign” or, less commonly, upgraded to “Pathogenic.” Studies have shown that the majority of reclassified VUS are found to be benign. This reclassification can happen months or years after the initial test, and patients are notified by their provider if a change occurs that impacts their medical care.