A new era in the interpretation of human genomic variation
Just five years ago, the world of variant interpretation was very different. There was no standard terminology for variant classification, and laboratories were using many different terms as ambiguous as “mutation” and “polymorphism” to convey pathogenicity, or lack thereof, and a plethora of qualifiers such as “possibly,” “probably,” and “likely” to convey degrees of uncertainty. The only terminology broadly agreed on was “variant of uncertain significance” (VUS). Furthermore, there was substantial variability in how laboratories evaluated evidence. A single publication in a peer-reviewed journal could be cited as justification for declaring pathogenicity, even though on many occasions little evidence to support that assertion was present in the publication beyond, for example, a non-statistically-significant observation in an affected individual. This was perpetuated by the routine deposition of “deleterious mutations” in the Human Gene Mutation Database,1 often without strong evidence supporting these claims. Similarly, exemplar variants included in the Online Mendelian Inheritance in Man database2 to support gene–disease relationships were assumed to be pathogenic.