As in silico analysis alone is not always sufficient to unambiguously assign VUS to either class II or class III, we would argue that the prospect of obtaining additional information from a family should be given more weight during the decision process preceding the communication of a VUS test result. Research initiatives such as the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), which strive to combine diverse sources of information, will be valuable in aiding a definitive classification of a VUS.