Distinct rates of VUS reclassification are observed when subclassifying VUS by evidence level

Genetic testing commonly yields a plethora of variants of uncertain significance (VUS) that can lead to ongoing uncertainty for patients and their caregivers. Although all VUS hold uncertainty, some VUS have more evidence in support of pathogenicity, whereas others have more evidence of a benign role. Sharing these nuances can help guide the investment in follow-up clinical and research investigations and may, at times, influence medical decision making despite appreciated uncertainty.

Four clinical laboratories have been subclassifying VUS to help prioritize investigation and guide reporting decisions. Each laboratory developed a distinct approach for how these subclasses are used in their laboratories and, in some cases, displayed on reports. We examined the composition of each laboratory's VUS subclasses and the likelihood variants from each subclass were reclassified toward pathogenic or benign.

We found that variants in the lowest subclass of VUS were never reclassified as likely pathogenic or pathogenic, whereas those in the highest subclass were much more likely to be reclassified as pathogenic or likely pathogenic.

Given that forthcoming professional guidance in variant classification will advise the use of VUS subclasses, the experience of our laboratories in using VUS subclasses can inform future practices.