Variants of Uncertain Significance in Vascular Anomalies: The Role of Reclassification

Vascular anomalies (VA) are rare developmental disorders due to somatic variants in intracellular growth signaling pathways. Although genetic evaluation is considered the standard of care for optimizing management, the frequency of variants of uncertain significance (VUS) in VA and their clinical implications are not defined.

Medical records were reviewed on all patients seen in our VA clinic from January 2014 to August 2024 with vascular malformations or related disorders who had undergone genetic testing. The year and patient age at the time of genetic testing, whether testing was done on peripheral blood or involved tissue, and results were noted. Laboratory vendors were queried about policies for reclassifying VUS and selective re-evaluations of VUS were requested.

In all, 154 patients underwent single gene or gene panel evaluations, with the number of patients tested increasing from zero in 2014 to 39 in 2023; 21 patients had testing done during the first 7 months of 2024. VUS were reported in 22 patients (14%). Many laboratory vendors maintain a policy of revisiting these nonpathogenic variants only when requested by the treating physician. Unsolicited reclassification was reported in a single patient whose VUS was found to be a normal variant. No changes were identified in six other patients whose VUS were re-examined.

VUS are not uncommon in VA. Reclassification may be possible as more variant-specific data become available and more testing is performed. Centers need to be aware that reclassification efforts are not automatic and should be considered where changes in therapy might result.