Moving targets in a static genome: The challenge of variant reclassification

This is the authors' abstract. We don't add key points for this paper.

Hypertrophic cardiomyopathy (HCM) is one of the most frequent “rare” inherited cardiac conditions, affecting roughly 1 in 500 individuals, and is often regarded as a paradigm condition for the application of clinical genomics. Since the discovery of the first disease-causing variant, MYH7 :p.Arg403Gln, in 1990 [ 1 ], genetic testing has become widely adopted and matured to the point where a positive result guides clinical decisions, especially for family screening through predictive cascade testing. Often times, for the sake of routine clinical practice, the result is dichotomised into actionable, (likely) pathogenic (LP, P) variants, or non-actionable: variants of uncertain significance (VUS), (likely) benign (LB, B) variants or no variants of interest. However, one could wonder what’s the warranty period of a result? We are used to challenging VUS periodically, but should we do the same for apparently disease-causing variants?