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What’s in a name? Classifying variants in our genetic code

The question: What does this report mean?

You are treating a patient you think has cystic fibrosis. You order full genetic sequencing for the gene that causes cystic fibrosis (CFTR), and the report reads: two variants identified, one “pathogenic” and one “variant of uncertain significance.” What does this mean? Does your patient have cystic fibrosis? Why aren’t all genetic testing results a clear “Yes” or “No” answer?

The challenge: How do we know the implications of genetic code changes?

In passing, we often think of medical answers as binary: You have a disease, or you don’t. Your test results are normal or abnormal.

In medicine generally, and in genetics specifically, it is often much more complicated. A change in the genetic code from a reference was previously referred to as a “mutation” but the current best practice is to label it as a “variant.” Due to the degree of normal variation between individuals’ genetic codes, it can be difficult to know if a specific variant is “abnormal” or “normal.”

Remember, when we look at the genetic code, we are trying to predict whether a change in the code will cause disease or is unrelated to how the gene functions. It is like trying to understand if a typo in a recipe will cause a kitchen disaster or cause an unnoticeable difference in taste.

The solution: Evidence, evidence, evidence – and your best estimate

To handle this ambiguity, genetic variants are categorized based on the level of confidence that the change in the genetic code is likely disease-causing or not. These categories are consistently labeled as “pathogenic”, “likely pathogenic”, “variant of uncertain significance”, “likely benign”, “benign.”

So how do variants get put into a category? There are guidelines to minimize personal judgment in choosing the categorization and many pieces of evidence are used1. One example: is this a common variant that many healthy people have? It is a huge job to review all the necessary evidence, and a team of variant scientists at Quest are pouring over primary literature, checking databases, and writing customized summaries to generate our genetic test reports

For your patient with possible cystic fibrosis, results only identified a single pathogenic variant. The other variant is a “variant of uncertain significance.” Two pathogenic or likely pathogenic variants would indicate a person has a genetic diagnosis of cystic fibrosis. Because your patient was found to have 1 variant of uncertain significance, it is uncertain whether a diagnosis of cystic fibrosis explains your patient’s symptoms or if it is another condition causing the patient’s symptoms. You could speak to a Quest genetic counselor and discuss why the variant was classified as uncertain or look for other methods of assessing for the condition (such as a sweat chloride test). Future research might lead to a recategorization of a variant's significance, so it is important to periodically check in with the laboratory to see if there is any new information.

At the end of the day, keep in mind that genetic categorizations are best estimates with the currently available evidence and that the test reports always need to be interpreted in the patient-specific clinical context.

To talk to a genetic counselor to learn more about variant interpretation, please contact Quest Genomics Client Services at 1.866.GENE.INFO (1.866.436.3463). Click here for the Quest Diagnostics Cystic Fibrosis Test Selection Guide


1Richards S., Aziz N., Bale S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-423.