Is There Potential Clinical Utility in Reporting Variants of Uncertain Significance From Prenatal Sequencing?
OBJECTIVE: Prenatal sequencing of fetuses with abnormalities detected on imaging is expanding globally. Debate continues over whether variants of uncertain significance (VUS) should be reported prenatally, with some recent national position statements opposing this. In England, VUS that fit the fetal phenotype and require little further evidence for upgrade are discussed at multidisciplinary team (MDT) meetings to determine whether to report. We review the VUS reported by one English laboratory that provides prenatal sequencing to half of England. METHOD: The laboratory's database was searched from 01/10/2020 to 30/04/2025 to ascertain all cases where a VUS was reported. Pregnancy outcomes were obtained from local clinical teams to determine whether the VUS status had been resolved. RESULTS: VUS were reported in 41/881 fetuses sequenced. Follow-up data were available for 38/41 cases, of which 23 were subsequently upgraded to likely pathogenic and 1 downgraded to likely benign. The most common reason for upgrade was new information from post-mortem or postnatal review (17/23). CONCLUSION: There is clinical utility in reporting VUS from prenatal sequencing following MDT discussion. Although reporting VUS leaves parents with uncertainty, follow up (including post-mortem when applicable) resolves this in over 50% of cases (79% of cases re-examined pre- or postnatally).