Nothing has caused more headaches and confusion in the world of genetic testing for cancer predispositions than the “variant of uncertain significance” (VUS), especially common now with the advent of multi-gene panels. But it’s possible that things are going to get worse before they get better. The very word (“variant”) that has caused more unpredictable counseling than anything else in genetic testing is – rather than getting demoted or kicked out of our lexicon – getting a makeover, so that it will be word-of-choice for all possible outcomes with genetic testing that are not completely “normal.” That’s right. More variants rather than fewer. We are in the middle of a transition to a new lexicon that is going to use the word “variant” (or “alteration” or “change”) for everyone who is not composed of perfectly normal DNA. Of course, with whole exome sequencing, everyone will have variants. Unlike the guidelines-of-choice that might vary from one organization to another, geneticists turn to a single source for their direction and their lexicon – the Human Genome Variation Society. And in their article published in Human Mutation 2016; 37:564-569, the HGVS had this to say about the need to abandon terms like “deleterious mutation” and “polymorphism”:
In contrast to the original recommendations, the terms “polymorphism” and “mutation” are no longer used because both terms have assumed imprecise meanings in colloquial use. Polymorphism is confusing because in some disciplines it refers to a sequence variation that is not disease causing, whereas in other disciplines it refers to a variant found at a frequency of 1% or higher in a population. Similarly, mutation is confusing since it is used both to indicate a “change” and a “disease-causing change.” In addition, “mutation” has developed a negative connotation (Condit et al., 2002; Cotton, 2002), whereas the term “variant” has a positive value in discussions between medical doctors and patients by dedramatizing the implication of the many, often largely uncharacterized, changes detected. Therefore, following recommendations of the Human Genome Variation Society (HGVS) and American College of Medical Genetics (ACMG) (Richards et al., 2015), we only use neutral terms such as “variant,” “alteration,” and “change.”
So, are we headed for the following in our genomic testing reports?
I -- Variant with strong propensity for phenotypic disease that might be considered not-benign
II – Variant with probable propensity…
III – Variant with possible or unknown propensity…
IV – Variant that is unlikely to be associated with phenotypic expression….
V – Normal
(feel free to substitute “alteration” or “change” for “variant”)
In this politically correct, kinder, gentler world, maybe a new lexicon is exactly what we need to get more people to sign up for genetic testing where we can manage disease before it happens. A “disease-causing variant” seems much more vulnerable to interventions than a rock solid mutation.
Yet, sometimes, these terminology proposals simply don’t fly. Clinicians are fickle when told to change their tune. Can we really practice medical genetics, though, without using the word “mutation?” And what’s next? Will the next superhero movie alter its title to the Teen-age Variant Ninja Turtles? Will the next blockbuster in 2018 be X-Men: The New Variants. Maybe it’s time for a change (or an alteration), but do we really want to camouflage the underlying clinical importance when one’s DNA is misspelled?