Variant of uncertain significance on prenatal microarray — structured clinical encounter

Station brief (candidate)

You are the paediatric registrar on the fetal medicine multidisciplinary round. Priya is 34 years old at 18 weeks gestation. Her mid-trimester anatomy scan showed bilateral ventriculomegaly. Amniocentesis was performed and the chromosomal microarray returned a copy-number variant classified as a variant of uncertain significance. She has Googled the finding and is frightened. She asks whether her baby will have a disability and whether she should "do something about it." You have 12 minutes with the patient and 5 minutes for examiner discussion. [6] [11]

Information available on request

• Second pregnancy; first child is well. No consanguinity; no relevant family history. [6]
• Bilateral ventriculomegaly at approximately 12–14 mm (mild to moderate) on the anatomy scan; no other structural anomaly identified. [11]
• Chromosomal microarray on amniocentesis: a copy-number variant classified as a variant of uncertain significance. The variant is a small duplication not previously reported as pathogenic or benign in the major databases. [1] [6]
• Clinical genetics has been consulted but the appointment is in two weeks. Priya is anxious and wants answers now. [6]
• Preferred language English; she and her partner are present. [6]

Tasks

1. Explain a variant of uncertain significance in plain language without equating it with either a diagnosis or a clean bill of health. [6]
2. Outline the steps that may clarify the significance of the variant, including parental testing and database review. [1] [6]
3. Address the misconception that a VUS means the baby will have a disability. [6]
4. Design a plan for ongoing ultrasound surveillance and multidisciplinary follow-up, with a named owner. [11]

Marking anchors

Must-hit

• States that a VUS is a real finding whose clinical meaning is genuinely not yet established — it is neither pathogenic nor benign by current evidence. [6]
• Offers parental testing: if the VUS is inherited from an unaffected parent, incomplete penetrance is more likely; if de novo, it is more likely to be significant. [1]
• Explains that the variant should not drive irreversible decisions without further clarification. [6]
• Uses plain language and teach-back: "Can you tell me in your own words what a variant of uncertain significance means?" [6]
• Plans ongoing ultrasound surveillance of the ventriculomegaly and books a clinical genetics appointment with a named owner. [11]

Merit

• Discusses database review (ClinGen, ClinVar, DECIPHER) and phenotype correlation as tools that may reclassify the variant over time. [6]
• Acknowledges the anxiety honestly without minimising or over-reassuring, and offers the option of serial ultrasound to monitor ventriculomegaly progression. [11]
• Discusses the possibility of exome sequencing if the VUS and ultrasound findings together suggest an underlying monogenic cause, while explaining that exome may find further VUS findings. [11]

Fail

• Tells the patient the baby will definitely be fine because the variant is "probably nothing." [6]
• Tells the patient the baby will definitely have a disability because "they found something." [6]
• Pressures the patient toward termination based on a VUS. [6]
• Discharges the patient without a booked clinical genetics appointment or a named owner. [6]