Transcript Mary Porteous - UK NEQAS for Molecular Genetics

VUS: The
clinician’s
view
Mary Porteous
On behalf of Scottish
Clinical Geneticists
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
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
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.
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
 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.
 In summary, sequence analysis demonstrated
the heterozygous sequence change --. This
sequence change is currently classed as a VUS
and further studies are recommended
 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.
 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.
 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
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?
Functional studies
 What test?
 What sample?
 What timeframe?
 What chance of a result?
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?”