Variants of Uncertain Significance: How Genetic Counseling Can Help Funnel the Uncertainty

I recently planted four new 3-gallon limelight hydrangeas in my front yard. It was a landscaping project I’d planned for at least a handful of years, so when it was finally completed I was more than excited.  Like a new parent, I water (feed) them daily and spend more time than I should obsessing over their health and “adjustment” to their new home. Are the leaves at the bottom turning yellow because they are over watered? Or is that “transplant shock”? Are they getting too much sun? Did a neighbor’s dog make an unwelcomed visit? How do I know if this is normal or if there is something I need to be doing? Each night I find a new concern to Google and hope the most concerning result does not apply.

Clearly, there are some elements of uncertainty that do not sit well with me. So, it should not come as a shock that today I’d like to tackle the issue of variants of uncertain significance (VUS) identified through genetic testing. Genes make products our bodies need, so we need them to “work.” Genetic testing is usually performed to find out if someone has a gene change that makes a gene not work. A non-working gene (or positive result) can cause a genetic disease or risk in a person. A person with a negative result, has no changes in the gene that cause it to not work.  So then what is a VUS, you ask? A VUS is a change in a gene, but at this point we don’t know if it makes the gene not work or if the gene is okay. It’s not a positive. It’s not a negative. It’s a “well, maybe.”

Maybes don’t tend to upset me when it has to do with the weather, meal planning or most of life’s other daily questions. But when the health of a loved one or my own health is in question, the maybe it’s no big deal but maybe it is a big deal is not as easy to handle. Advances in genetic testing technology mean it is now possible to evaluate many genetic sequences using one small sample. The costs have come down and the results might even come back before the new pair of shoes you ordered arrive. However, the speed, cost and breadth of testing options are only truly beneficial when the results that are returned are meaningful to you and your health.  VUSes are not; they are the literal and figurative unknowns.

The good news is that the vast majority (likely 90%, studies say) of VUSes will be reclassified over time as benign. Most will end up as common human variations, that just make us “us.” But some will ultimately be reclassified as pathogenic and disease causing. How can we keep from going crazy when even the “experts” don’t know which are which? Given that the clinical significance of VUSes are not known, individuals who have a VUS in a cancer susceptibility gene are most often advised to undergo cancer screening based on their personal and family history alone (NOT the gene the VUS was found in). It’s a blindfold approach: a “pretend you don’t know it’s there” kind of thing. But that may be easier said than done.

A recent study in the Journal of Clinical Oncology (Kurian et al. 2017) found that up to half of breast cancer patients who undergo bilateral mastectomies as treatment following genetic testing, were not found to have a pathogenic gene mutation indicating a higher risk of additional malignancies but a VUS instead.  The study’s author concluded that this finding suggests that many women and their doctors aren't interpreting the results of genetic testing properly.

VUSes aren’t restricted to the cancer setting either. Pregnant women who under diagnostic testing may receive a chromosomal microarray test with a copy number variant of uncertain significance result, leading to significant worry about the health of an unborn child and possibly ethical dilemmas in decision making regarding termination of pregnancies.  Families with children seen in pediatric genetics clinics may receive multiple VUS results in multiple genes through genome or exome testing of their child with developmental delay. Are these VUSes the cause of the ailments in their families and something that can be used in future pregnancy planning? Or are they benign and just convenient but incorrect targets of our desire to find the reason for the problem?

Genetic counselors can play a critical role in helping individuals and families interpret what is and perhaps just as importantly what IS NOT known about a particular VUS. They like (it’s true!) to read the extra-long paragraphs at the end of the results and frequently make calls to the labs themselves to gather more information. And when very little or nothing is known, genetic counselors can walk you through the best plan for you based on where your goals for the testing began and what may come later on.

I may not be able to predict whether my hydrangeas make it through the first hot week of the summer, my clay filled soil or can handle Chicago winters. But as my husband tells me, “maybe” this time I’m better off asking an expert directly. Or at least, that’s how I’ll start my email to our family expert and landscape architect, Clare.

Please contact us at 312-981-4400 if Insight’s genetic counselors can help you clarify your genetic testing results.