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Variants of Unknown Significance

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In a small number of cases, genetic testing finds a “variant of unknown significance,” or VUS. This means there is a portion of the gene that looks different from the way it’s normally expected to look. However, researchers haven’t yet confirmed whether this variant is a harmless change or a risk factor for cancer. The variant remains on a “watch list” as researchers collect information to determine whether or not people who have it are at increased cancer risk.

“They actually do basic research as well as studies within families to determine whether the variant is damaging or not. Over time, variants get reclassified as to whether they’re mutations or just normal variations,” notes Cristina Nixon, M.S., LCGC, a licensed certified genetic counselor with the Cancer Risk Assessment and Genetics Program at Main Line Health in Pennsylvania. Nixon notes that the rates of VUS results vary depending on the gene. For example, the rate of a BRCA1 or BRCA2 VUS varies from 2 to 4% depending on the laboratory performing the testing. Sometimes a VUS is also referred to as an “inconclusive” finding.

If you have a variant of unknown significance, your genetic counselor will work with you to interpret that result in relation to your family members’ cancer history and their genetic test results. If many relatives are tested and found to have the same variant, then it may be responsible for the increased cancer risk in your family. On the other hand, if your relatives all share a mutation already known to be harmful, your VUS may be less concerning. “In either case,” Nixon says, “a VUS cannot be interpreted based on your family history alone. Some laboratories will study a VUS within a family to see if it is tracking with cancer. The more families with the VUS who are able to participate in a study, the more data the lab will have, which assists in determining whether the VUS is a mutation or normal gene variation.” If you don’t have many (or any) other relatives who have been tested, your genetic counselor can help you figure out how to use your family history and genetic test results. Together, you might decide based on family history that you should follow at least some of the recommendations given to women at high risk of developing breast cancer.

Getting a VUS result is a good reason to keep in touch with your genetic counselor. Most testing companies will update your genetic counselor, who will update you, if research reveals that the variant is associated with an increased risk of cancer. You also can check in periodically to see if there has been a change in the available information.

Cristina Nixon has found that people react differently to the news that they have a variant of unknown significance. “Some people are just so glad to hear that they don’t have a known harmful mutation and they stop listening after that point, and sometimes they just forget about it,” she says. “I’ve called people to give them updated information, and they had forgotten they even had a variant! But I have others who get really concerned about it. It bothers them to know that something is there, but we don't know if it means anything or not.”

Because the science is always changing, Nixon adds, there can be rare instances in which two different testing companies classify the very same genetic alteration differently: One might label it a variant of unknown significance, while another classifies it as harmful. This is often a matter of judgment, with one lab deciding there is enough evidence that the mutation is linked to higher cancer risk, while another decides more evidence is needed. Your genetic counselor can help you understand your results and what to do with them. For example, if your family members all received a positive mutation result from one testing company, and you were told by another company that you have a variant of unknown significance, this is worth further investigation.

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