Mutation. What images does the word conjure up for you? Genetic counselors have long avoided using this term in clinical practice due to its similarity to the word “mutant”, favoring instead the vague but people friendly term “changed gene”. In fact, there is a far more scientific reason for clinicians to avoid using the term “mutation”, and that is the definition of the word itself.
Mincing words. By definition, a mutation is a permanent change in the nucleotide sequence of DNA. Notice what is missing in that definition — any suggestion that said permanent change is disease-causing. A nucleotide change can be permanent, but have no impact on gene structure or function. There has been a de facto but erroneous assumption of pathogenicity associated with the term mutation, just as there has been an assumption of benign impact associated with the term “polymorphism”. In fact, a polymorphism is defined as a DNA variant with a frequency above 1%. Thus, just as a mutation may be benign, a polymorphism, though present in some percentage of individuals, may be disease-causing.
The new nomenclature. The confusion over incorrect assumptions about the meaning of “mutation” and “polymorphism”, used for decades in clinical practice and laboratory reporting, led the American College of Medical Genetics and Genomics and the Association for Molecular Pathology to issue new guidelines for the interpretation of sequence variants in 2015. The details of the recommendations will be the subject of the next EpiGC post in April, but briefly the guidelines call for the replacement of both “mutation” and “polymorphism” with the term “variant”. Those of you who routinely order molecular testing may have already noticed the change in reporting. Results are now to be classified as variants that are pathogenic, likely pathogenic, of uncertain significance, likely benign, or benign.
What’s in a name? You might be wondering why any of this matters. Aside from my own bias against using language that could be considered potentially offensive or shaming by patients and families, the most critically important purpose of these new guidelines is an attempt at consistency, which is so badly needed in the field of epilepsy genetics. Variant interpretation is an art that takes into account many factors. Variants may be re-classified over time, yet I’ve seen clinicians perpetuate the idea of confirmed pathogenicity in the medical record by referring to variants of uncertain significance as “mutations”. This gets repeated by other providers and before you know it years have passed with a presumed “diagnosis” having been made erroneously. The thing is, families understandably often become very invested in a diagnosis, seeking community and support from gene-specific organizations. The diagnosis provides an identity, an explanation, a purpose for families inclined toward participating in efforts to raise awareness or funds for research. I’ve seen what happens when a variant is re-classified and a diagnosis is “taken away”. It can turn a family’s world upside-down in a moment. And what about the potential impact on treatment decisions or participation in clinical trials? Families want the benefits of molecular medicine, but sloppy and imprecise communication of information may be far worse than no information at all.
Just do it. The promises of precision medicine in epilepsy genetics are tremendous and we are all motivated by a desire to help the families that we serve, which hinges largely on the success of molecular testing and variant interpretation. As clinicians we have a responsibility to be as precise in our language as the laboratories that provide us with test results. So – read those reports carefully. Educate yourself about what goes into variant classification. Make sure the families you serve understand the nuances and limitations of the information you are providing to them. Be mindful of the language you use in documenting test results in the medical record and patient letters. And please – stop using the term “mutation”!