Prenatal Variants of Uncertain Significance (VUS): to report or not to report?

Prenatal Exome Sequencing (pES) has a significant diagnostic yield but time pressure and limited phenotypic information make interpretation of Variants of Uncertain Significance (VUS) more challenging than in a postnatal setting. We share our experiences of prenatal reporting of highly suspicious VUS. We retrospectively analyzed pregnancies in which VUS identified by pES were reported to parents during pregnancy in two Dutch academic medical hospitals. During the study period, 31 VUS in 28 genes were reported in 27 pregnancies. Cases were assigned to one of five groups based on consistency of prenatal phenotypes with gene-associated diagnoses. The implications of VUS included clinical evaluation of parental carriers (N = 4), additional screening of proband (N = 2), influencing parental decision-making (N = 11) and/or prompting confirmatory testing (N = 10). Reanalysis with currently available data resulted in reclassification of seven variants, five of which were upgraded to (likely) pathogenic. Although we do not recommend routine disclosure, our data suggest that prenatal reporting of VUS can be valuable in exceptional cases. Stringent selection was applied and only a minority of reported VUS was reclassified as (likely) pathogenic. Therefore, a careful individual assessment of each VUS case remains imperative and multidisciplinary meetings should be an integral part of prenatal VUS management.