PROX1 and lymphedema: Although both variants are presently classified as VUS according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines (Richards et al., 2015; https://varsome.com/), considering their extreme rarity in the general population and the concordant results of bioinformatics prediction tools as well as our own molecular modeling of mutant PROX1 protein, we propose that these two missense variants, identified in our patients, result in at least partial loss‐of‐function of PROX1 and predispose to lymphedema.