Variants of Uncertain Significance (VUS) in Rare Disease: What Every Provider Should Know

Genetic testing can provide life-changing answers for patients with suspected rare genetic conditions. But sometimes, results aren’t definitive. A genetic test may identify a Variant of Uncertain Significance (VUS), which means a genetic change was identified, but there isn't enough evidence yet to determine whether it is harmless or disease-causing.

For providers, a VUS can create uncertainty because it neither confirms nor rules out a diagnosis. Fortunately, many VUS are eventually reclassified as new evidence emerges. Rather than a dead end, a VUS is the starting point for gathering additional evidence that may lead to a definitive answer.

 Why Variants are Classified as Uncertain

A VUS is reported when the available scientific evidence is limited or conflicting. For example, a variant may occur in a gene known to cause disease, but that exact change may never have been seen before. Without sufficient clinical or functional evidence, genetic testing partners cannot determine with certainty whether the variant is disease-causing or harmless.

To communicate that level of certainty, genetic test reports follow the widely accepted American College of Medical Genetics and Genomics (ACMG) variant classification system¹:  Benign → Likely Benign → VUS → Likely Pathogenic → Pathogenic 

A VUS remains in this middle category until enough evidence is available to confidently reclassify it.

 How Should Providers Interpret a VUS? 

According to ACMG guidelines, a VUS should not be used to guide clinical decision-making¹. Medical management should instead be based on the patient's clinical presentation, family history, and other available evidence while additional data are gathered.

Although a VUS can be frustrating, uncertainty is preferable to an incorrect classification. Calling an uncertain variant Likely Benign too soon may prematurely end the diagnostic search. Conversely, incorrectly classifying it as Likely Pathogenic could lead to unnecessary testing, treatment, or anxiety for patients and families.

Instead, the goal is to gather the evidence needed to confidently reclassify the VUS.

How a VUS is Resolved — and how MyOme Gets Ahead of Uncertainty

Resolving a VUS often requires additional evidence gathered over time through collaboration between the provider, patient, and genetic testing partner. MyOme tests are designed to incorporate many of these evidence-building strategies upfront, helping reduce uncertainty even before the report is delivered.

1. Comprehensive Testing

Advanced genomic technologies—such as whole-genome sequencing, long-read sequencing, or multiomic analysis—can provide supporting evidence that helps determine whether a VUS is disease-causing.

• How MyOme Gets Ahead of Uncertainty: Our comprehensive diagnostic tests use whole-genome sequencing, long-read sequencing, and methylation analysis to resolve variants that may remain uncertain with traditional gene panels or traditional exome tests.

Testing blood relatives (especially parents or siblings) provides vital context. Determining if a variant was inherited from an unaffected parent or if it appeared de novo (completely new in the patient) can provide strong evidence for whether it is disease-causing.

• How MyOme Gets Ahead of Uncertainty: We strongly encourage family testing (via our duo and trio testing options) whenever possible because family data significantly improves variant interpretation and reduces VUS rates compared to proband-only testing.²

3. Ongoing Variant Review

Genetic knowledge is constantly expanding. As new scientific publications, clinical databases, and reported cases emerge, previously uncertain variants may be reclassified.

• How MyOme Gets Ahead of Uncertainty: Every patient's genome is sequenced once and retained for future analysis. As new gene-disease relationships are discovered, MyOme can reanalyze existing genomic data using updated algorithms that incorporate the latest scientific evidence, without requiring another sample or repeat sequencing.

4. Reanalysis as the Clinical Picture Evolves

Variant interpretation depends on a patient's clinical symptoms and medical history, which help guide which genes and variants are prioritized during analysis. If a patient develops new clinical features over time, this can expand the scope of genomic analysis and improve interpretation.

• How MyOme Gets Ahead of Uncertainty: As clinical presentations evolve, MyOme can reanalyze existing genomic data using updated phenotype information to expand the analytical scope and uncover new evidence that may help reclassify a VUS, without requiring a new sample or repeat sequencing.

The MyOme Difference

While MyOme reports all clinically relevant VUS, our philosophy is to do everything possible to reduce uncertainty before a result is reported. We start with advanced genomic technology, incorporate family testing, and enable seamless reanalysis to maximize the opportunity to resolve uncertain variants.

When the available evidence still isn't sufficient for a definitive classification, we believe reporting a VUS is the most clinically responsible thing to do. Every reported VUS reflects a thorough review by geneticists, PhD scientists, and genetic counselors using the latest available scientific evidence. For patients undergoing diagnostic testing, an uncertain finding may become an important piece of the puzzle as new evidence emerges.

Of note: This philosophy differs for MyOme Proactive Health tests. Because proactive risk screening is performed in generally healthy individuals, we report only pathogenic and likely pathogenic variants (not VUS) to provide clear, clinically actionable results while avoiding unnecessary anxiety and confusion.

The Bottom Line

A VUS is not a diagnosis, a negative result, nor the end of a diagnostic journey. It reflects the current state of available evidence and should not be used alone to guide clinical decision-making.

Thorough genetic testing isn't about avoiding VUS at all costs. It's about doing everything possible to reduce and resolve them.

References

1. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30.
2. Rehm HL, Alaimo JT, Aradhya S, et al. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change. Genet Med. 2023;25(12):100947. doi:10.1016/j.gim.2023.100947.