Yvonne Wallis
UKNEQAS for Molecular Genetics
Unclassified Sequence Variants Participants Meeting
Edinburgh 01.03.13
UV Best Practice Meeting
April 2007 NOWGEN
CMGS/Dutch labs/Special guests
Jennie Bell/Simon Ramsden
Draft Updated Guidelines
February 2013
Interpretation & Reporting of Rare
& Novel Variants
1st Best Practice Guidelines
January 2008
Interpretation & Reporting of UVs
Follow up Best Practice
Meeting
UKNEQAS UV Participants
Workshop
March 2013
Final Updated Guidelines
March 2013
Interpretation & Reporting of Rare
& Novel Variants
March 2011 Birmingham
CMGS labs
Pathogenicity of sequence
variants interpretation
Pilot EQA scheme
2012
Follow up best practise meeting March 2011
 2008 guidelines in place for 3 years
 Very good base-useful and were used/referenced
 Embedded within our discipline
 Facilitated a more standardised approach within labs to variant
assessment
 Time to review them
 Still accurate?
 New information?
 Reflect actual practice?
 Was there consistency across labs?

Do labs apply/use common strategies/rules?
 Uncertainty about the use of in silico tools
 How to use them
 Trust them/apply them
 Meeting aim-review each section in turn to expand and consolidate
where necessary
Revision process: to produce 2013 DRAFT version
 MEETING-2011
 Each section reviewed/discussed
 Changes agreed
 Individuals nominated to make changes as appropriate
 Kathryn Robertson coordinated revision process
 POST MEETING
 Dutch lab members reviewed
 Further reiterations
 Lots of changes
 Final draft Feb 2013 (YW-used judgement and common sense!)
 Please flag errors
 Today or yvonne.wallis@bwhct.nhs.uk
2013 DRAFT guidelines-what next?
 Number of outstanding issues
 Overlap with outcomes from UKNEQAS UV pilot scheme 2012
 TODAY
 Coming together
 Reach consensus
 Recommendations incorporated in to the final version
 OVER LUNCH:
 New Title:

Reporting and Interpretation of Rare or Novel Sequence Variants
 Terminology:


Use of “Variant of uncertain significance”
Use of VUS (VOUS suggested by Dutch reviewers)
What’s new and requires further discussion in v2?
 4.2 Presence or absence on SNP Databases
 Section promoted and extended
 Additional information
 Useful/accurate/problems?
 What rules do labs use to assign benign polymorphism?
 4.5 Co-segregation with the disease in the family
 Inclusion of SISA



Simplified method for segregation analysis
Background information or potentially useful?
Criteria for it’s implementation?
What’s new and requires further discussion in v2?
 4.7 Species conservation
 Significantly expanded

Lots of new references
 Does it need more?
 Nucleotide conservation?
 Use of PhyloP and PhastCons tools?
 How much weight do labs put on this?
 Do labs create gene specific MSAs?
 4.8 In silico prediction of pathogenic effect
 Significant modification


New references
Is this sufficient to support labs?
 How much weight do labs put on this?
 Do labs validate tools using variants with known effect?
What’s new and requires further discussion in v2?
 4.9 In silico splice site prediction
 Significantly expanded
 Additional references included
 Alamut mentioned within this section



Note of caution
Is this enough?
Should instructions be included on how to use the software?
 Is information on scores of the prediction tools needed?

Should there be suggested criteria for changes in scores
supporting consistent follow up studies?
 E.g., 10% deviation from the wild-type score
What’s new and requires further discussion in v2?
 5.4 Classification of variants
 Number of outstanding issues related
 4 vs 5 class system



Dutch reviewers recommend 4 categories
UK team prefer 5 categories
Overlap with NEQAS scheme outcomes
 Should/could a common preferred system be implemented



Common definitions
Common wording
Common recommendations for follow up studies
Final Thoughts
 Lots of amendments
 Lots of helpful information
 IMPORTANT to close off outstanding issues
 Never going to be perfect-evolving
 TODAY-NOT a full BP meeting
 Consensus from guidelines and NEQAS outcomes
 1st BPs to be ratified by ACGS
Acknowledgements
 Participants attended the follow up BP meeting 2011
 Kathryn Robertson
 Andrew Devereau
 Stewart Payne
 Ciaron McAnulty
 Dutch lab colleagues