Variants of Uncertain Significance
Should We Revisit How They Are Evaluated and Disclosed?
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See Article by Hellwig et al
Multigene panels for cardiogenetic conditions are cost-effective and informative when pathogenic variants are identified, but can become a source of frustration and potential misunderstanding when the result is a variant of uncertain significance (VUS). One of the 5 variant classification categories recommended by the American College of Medical Genetics and Genomics (ACMG),1 a VUS classification means that there is insufficient or conflicting evidence about a molecular alteration’s role in disease. Variant classification, as established by ACMG consensus, requires evaluating differently weighted pathogenic and benign criteria, then combining these criteria using a scoring rubric. The process can result in 1 of 5 classifications: benign, likely benign, VUS, likely pathogenic, and pathogenic (Figure).
A VUS classification is not an uncommon result in cardiovascular genetics. A recurring scenario is that of a new variant identified in a gene where other pathogenic variants are known to cause a condition. The variant, found in one patient who has the condition, is absent in reportedly unaffected individuals according to reference databases. Evolutionary conservation data suggests that the location where the variant occurred is well-conserved throughout species, suggesting that the location does not tolerate variation. Although this evidence supports pathogenicity, the variant has only been seen in one patient, …