One question I sometimes get about genetic testing is, “What’s the downside?” Aside from potentially finding out something really scary about yourself, you could be presented with something you weren’t expecting: more confusion.

We tend to think about test results as a yes or no answer. You either have a gene (or more accurately, a mutation in a gene), or you don’t. Now there are lots of scenarios where you might have a gene mutation, but the way it affects you could range from not at all to very severe. That’s not what I’m talking about here. I’m talking about getting a result on a genetic test, but geneticists don’t know what it means. I mean any geneticist, anywhere; not just yours. It’s a result that’s either never been seen before, or seen so infrequently that we don’t know enough about it to decipher it.

3 different colored eyes

This happens more often than you might think. Every human on Earth is different, and genetic variation is responsible for all those differences, both benign and medically significant. I’ll use eye color as an example. One of the key genes in determining eye color is called OCA2. The version of OCA2 that I have makes my eyes blue. The version of OCA2 that my husband has makes his eye brown. Neither one of us have an eye disorder. His eye color isn’t better than mine. It’s just different. But which version should we call “normal”? Well, both. We call these inconsequential differences “polymorphisms.” When we do genetic testing, we have a list of known polymorphisms that are different versions of normal, and we have a list of known mutations that cause disease. The problem is when we find a version in a person that isn’t on either list. We call these versions “Variants of Uncertain Significance” or VUS.

What happens next?

First, there’s lots of weeping and gnashing of teeth. Then we get back to work trying to analyze how this version of the gene might affect the body. We look at the same gene in a bunch of other species to see if that particular region of it is the same across all of them. If it is, we have to assume it’s pretty important that section stays intact or bad things happen. We can also use computer models and lab experiments to try and see if this version of the gene could still be functional. Other family members could be tested to see if the other people in the family who have the same condition all have the same version of the gene. All this takes time, and sometimes we still can’t tell which list this version should be on. In those cases, we can’t call it either way. The patient just has to sit and wait until enough data is gathered to give us an answer. This can take years!

Man Screaming
How I feel when we get a VUS result


This incredibly frustrating scenario is more likely to happen when the test is relatively new. It also is more likely to come up when the person being tested is not white. That’s simply because we’ve looked at more white people’s genes in this country than we have people of color. We have more data, longer lists of known polymorphisms, that have come from other white people. As more and more diverse people have genetic tests done, our list of known “normals” will grow and we should have to deal with this scenario less and less. Or at least I hope so.


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