Uncertain Results Related to Patient Symptoms: Variants of Uncertain Significance

Key Points:

  • Variants of Uncertain significance have an uncertain relationship to disease.
  • It is not recommended that Variants of Uncertain Significance be used for clinical decision making.
  • International efforts are underway to reclassify VUS variants as benign or pathogenic.
  • Finding a VUS is common among large-scale tests like gene panels, whole exome, and whole genome sequencing.
Genomic variants are typically classified on a five-point scale to indicate the
likelihood that the particular variant is associated with disease.

Genomic variants are typically classified on a five-point scale to indicate the likelihood that the particular variant is associated with disease.

Sequencing of a gene can identify variants that are different from the reference sequence, yet not well understood. In contrast to genetic variants that have been confirmed to be associated with increased risk for developing a disease, a Variant of Uncertain Significance (VUS) has an uncertain relationship to disease.

There are several reasons why variants are classified as VUS, such as:

      1. The effect of the specific genetic alteration on gene function is not known.
      2. There are insufficient genetic data to definitively confirm that the variant is associated with risk of developing the disease.
      3. The patient is unaffected and has no symptoms, or different symptoms than those expected based on the variant found.

As more data accumulate over time, a VUS may be reclassified to likely pathogenic or likely benign. Until a VUS is reclassified, clinicians are advised not to use a VUS result for clinical decision-making. Further, the American College of Medical Genetics and Genomics (ACMG) recommends against using a VUS result for genetic testing in at-risk relatives because the meaning of the result is uncertain. However, testing of certain relatives can sometimes provide useful data to the testing laboratory to aid in the eventual reclassification of the variant.

International efforts are underway to systematically review all genomic variants, with the objective of reclassifying VUS results according to best practice guidelines. Many clinical genetic testing laboratories will, as a matter of policy, issue an amended report when a VUS result is reclassified to a category considered clinically actionable, and these amended reports are usually sent to the physician who ordered the test. As reclassification of a VUS may occur years after the original test was performed, clinicians and patients may consider re-contacting the laboratory that performed the genetic testing periodically for updates. In addition, resources are available online that enable clinicians to explore variants identified in their patients. For example, ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/) is a robust online resource that catalogues the classification of specific genetic variants, submitted by genetic testing laboratories and experts.

In the case of genetic tests that examine multiple genes, such as multigene panels, whole exome sequencing, and whole genome sequencing, the likelihood of finding one or more VUS is high; some studies report VUS in as many as 1 in 3 patients2. Individuals undergoing multigene sequencing tests should receive pre-test education about the fact that such testing increases the likelihood of a VUS result. In addition, patients of a non-Caucasian ethnic background that has been less well characterized have an increased likelihood of VUS results.

A 39-year-old woman diagnosed with breast cancer undergoes gene sequencing for alterations in the BRCA1 and BRCA2 genes and is found to carry a variant of uncertain significance (VUS) in BRCA2. Two years later, the woman is diagnosed with another cancer - a sarcoma. She undergoes genomic sequencing of both tumor DNA and germline DNA (healthy, non-tumor DNA). Her germline DNA result shows a pathogenic variant (or mutation) in the TP53 gene, a well-known tumor suppressor gene associated with Li Fraumeni syndrome. This new information confirms a diagnosis of Li Fraumeni, a hereditary cancer syndrome characterized by strikingly increased rates of cancer, in this patient.

Further review of data on the initial BRCA2 variant shows that this variant is now known to be commonly observed in individuals of Asian ancestry and has been reported in 5 individuals who were also confirmed to carry pathogenic mutations in other cancer-associated genes. As a result, the BRCA2 variant is reclassified as “likely benign.”

The initial genetic test identified a VUS in BRCA2. Although BRCA2 is one of the most common genes implicated in breast cancer, the variant was classified as a VUS because of insufficient information. The fact that a pathogenic germline mutation in TP53 was subsequently identified in this patient helped confirm that the BRCA2 VUS was likely benign. This woman’s family members should be offered testing for the pathogenic TP53 variant to help assess their cancer risk. Had testing for the BRCA2 VUS been offered to the family members their test results would have been misleading, since it is the germline TP53 pathogenic variant, not the BRCA2 VUS, that is responsible for the increased cancer risk in this family.

Next Steps to Consider

  • Referral to genetic services (medical geneticist and/or genetic counselor) for medical evaluation and in-depth discussion of the identified genetic variant
  • Contact the testing laboratory periodically for reanalysis of the genetic variant to determine whether more is known about its disease association
  • Explore current knowledge about the specific genetic variant utilizing resources such as ClinVar
  • Identification of relevant research studies specific to the gene or variant identified
  • Consider periodic reanalysis of genomic test data as knowledge and databases used in analysis improves over time



  • ClinicalTrials.gov (https://clinicaltrials.gov/): a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world.
  • ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/): a public archive of reports about the relationship between specific genetic variants and associated phenotype (symptoms).
  • National Society of Genetic Counselors (http://nsgc.org/): the professional organization for genetic counselors, with patient and provider resources and a searchable tool to “find a genetic counselor” near you.



  • Richards S. et al. Standards and Guidelines for Interpretation of Sequence Variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and Association for Molecular Pathology. Genetics in Medicine (2015); 17: 405-423.
  • Domchek, S. Multiplex Genetic Testing for Cancer Susceptibility: Out on the High Wire without a net? J Clin. Oncol. 2013; 31: 1267-70.