Patients approach genetic testing, either for germline (inherited) or somatic (tumor) alterations, hoping it will provide valuable information about their cancer risk, prognosis, or treatment options. Next-generation sequencing (NGS) makes it possible to test for panels of 40 or more genes simultaneously. By testing more genes, the possibility of finding an actionable, informative result improves, but so does the chance of having a result with one or more variants of unknown clinical significance (VUS).

What Are VUS?

A VUS does not provide enough data to determine whether a genetic change is a harmful (pathogenic) or harmless (benign). Every human has many common changes in their genetic makeup that are benign and do not affect cell function. These are called polymorphisms and account for human variability. Over time, enough data will emerge to determine if a VUS is a pathogenic or benign change.

VUS are not uncommon, and patients need to be prepared for the possibility of finding one during genomic testing. In a study of 1,197 individuals undergoing NGS in 36 genes associated with hereditary breast cancer, approximately 35% have one or more VUS.

Strategies to Evaluate a VUS

Evolutionary conservationism: tracks changes in protein dysfunction and increased risk for disease that occur when a specific protein sequence has been maintained throughout evolution in multiple species
Functional assays: directly or indirectly assesses the influence of a specific variant sequence on protein conformation or function using laboratory methods
In silico analysis: uses algorithms that digitally altering sequences to determine whether it alters protein function
Literature evaluation: reviews case reports and other reports in the literature regarding clinical implications of the genetic change
Population frequency: searches whole exome databases of sequencing data in families without a history of cancer to determine how often a variant has been seen
Segregation analysis: considers whether a VUS tracks within families with a diagnosis of cancer

Note. Based on information from Macklin et al. and Mahon.

The result can be confusing because a VUS is not actionable. In most cases, the VUS will eventually be downgraded to likely benign or benign, but reclassification can take years. Until the variant’s meaning is clear, recommendations for care are based on personal and family history of malignancy. Genetics professionals can access databases such as CLINVar or review the literature to obtain information about the VUS. Laboratories use multiple strategies to reclassify a VUS, and the information is included in the test report.

What Can Patients Do With Information About VUS?

When a VUS is found, a genetics professional may contact the laboratory to gather information and determine whether the family is eligible for family studies. Sometimes if another family member is diagnosed with cancer, the laboratory will offer testing to help clarify if the VUS tracks with cancer. Families may qualify for enrollment in research studies to aid in reclassification, such as the Prospective Registry of Multiplex Testing.

Testing family members outside of a variant reclassification study is not recommended because VUSs’ meanings are not clear. Although we’re tempted to believe that variants found in tumor cells could contribute to cancer progression, the reality is that a VUS is not a meaningful result and cannot guide therapy.

Most genetics professionals recommend that patients check in every 12 months to see whether more is known about the variant. If a variant is reclassified, genetics professionals will attempt to contact the patient. This is especially important if it is reclassified as pathogenic, because patients will have new recommendations for care and other family members may need testing.

Topics: