VUS: The clinician’s view Mary Porteous On behalf of Scottish Clinical Geneticists.
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Transcript of VUS: The clinician’s view Mary Porteous On behalf of Scottish Clinical Geneticists.
![Page 1: VUS: The clinician’s view Mary Porteous On behalf of Scottish Clinical Geneticists.](https://reader035.fdocuments.in/reader035/viewer/2022062318/551bc129550346b4588b4aae/html5/thumbnails/1.jpg)
VUS: The clinician’s view
Mary PorteousOn behalf of Scottish Clinical Geneticists
![Page 2: VUS: The clinician’s view Mary Porteous On behalf of Scottish Clinical Geneticists.](https://reader035.fdocuments.in/reader035/viewer/2022062318/551bc129550346b4588b4aae/html5/thumbnails/2.jpg)
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
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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
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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.
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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
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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.
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In summary, sequence analysis demonstrated the heterozygous sequence change --. This sequence change is currently classed as a VUS and further studies are recommended
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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.
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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.
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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
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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?
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Functional studies
What test?
What sample?
What timeframe?
What chance of a result?
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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?”