Clinician's View on Variant of Uncertain Significance (VUS) in Genetic Reports

1. VUS: The clinician’s view Mary Porteous On behalf of Scottish Clinical Geneticists

2. Data gathering • Contacted clinical geneticists and genetic counsellors across Scotland for input • Reviewed 600 reports sent to SE Scotland Clinicians • VUS significant problem • Numbers similar to pathogenic variants

3. VUS in 2012/13: The report • What we like • Classification of VUS more consistent • Interpretation guidance clearer • Evidence for classification either documented clearly on report or available from laboratory • What needs further consideration • Family studies • Functional studies • ? Predominantly Scottish issue

4. Recessive VUS • Although – and – have not previously been reported in the literature they represent 2 changes in a recessive gene that has previously been described in (Disease) consistent with (patient name) phenotype. Therefore we would strongly recommend testing of (patient) parents for – and – to confirm these changes are in trans.

5. Missing clinical information • This sample was analysed by direct sequencing of the LDLR gene. There is no evidence for the presence of the –VUS previously identified in an affected family member. As the sequence change is currently classified as a VUS the significance of the result for this patient is unclear. Knowledge of cholesterol levels prior to treatment if relevant will help ascertain the effect of the variant in this family

6. Please note that direct sequence of a fragment of (Disease gene exon) demonstrated the heterozygous sequence change --. However current evidence (ref Alamut) suggests that this variant is unlikely to be pathogenic. Please contact the laboratory if further information is required.

7. In summary, sequence analysis demonstrated the heterozygous sequence change --. This sequence change is currently classed as a VUS and further studies are recommended

8. Confirmation that this variant segregates with (Disease) in other family members would further support its pathogenicity and should ideally be undertaken prior to predictive testing in this family.

9. The pathogenicity of the – variant remains indeterminate at present. Analysis of other affected and unaffected family members for the – variant is available and may help clarify pathogenicity.

10. Further Possible investigations • Family studies may help to provide further evidence regarding the possible pathogenicity of this variant. We recommend testing --- parents in the first instance (if available) to determine whether this variant has arisen de novo. We could also test any additional family members

11. Family studies • Which relatives should be targetted? • How are the results fed back? • What is the information content of a family? • Whose responsibility for collating results? • Does it do any good? • Who pays for the analysis of other family members?

12. Functional studies • What test? • What sample? • What timeframe? • What chance of a result?

13. Conclusions • Recent reports on VUS are clearer and more homogeneous • Clinical Geneticists like to know how a conclusion was reached – share the pain • Don’t hide caveats in tiny print • Less experienced clinicians can struggle and need clear guidance on use of information • Please avoid the word “should” unless the action is clearly possible • We need to establish guidelines for family studies and to modify reports accordingly • All families/diseases are not equal – ask “will family studies really solve this one?”