yvonne wallis ukneqas for molecular genetics unclassified sequence variants participants meeting...
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Yvonne Wallis
UKNEQAS for Molecular Genetics Unclassified Sequence Variants Participants
MeetingEdinburgh 01.03.13
UV Best Practice Meeting
April 2007 NOWGENCMGS/Dutch labs/Special
guests Jennie Bell/Simon Ramsden
1st Best Practice GuidelinesJanuary 2008
Interpretation & Reporting of UVs
Follow up Best Practice Meeting
March 2011 BirminghamCMGS labs
Draft Updated Guidelines
February 2013Interpretation & Reporting of Rare & Novel Variants
UKNEQAS UV Participants WorkshopMarch 2013
Pathogenicity of sequence variants
interpretation Pilot EQA scheme
2012
Final Updated GuidelinesMarch 2013
Interpretation & Reporting of Rare & Novel Variants
Follow up best practise meeting March 20112008 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 versionMEETING-2011
Each section reviewed/discussedChanges agreed Individuals nominated to make changes as appropriateKathryn Robertson coordinated revision process
POST MEETINGDutch lab members reviewedFurther reiterationsLots of changes Final draft Feb 2013 (YW-used judgement and common
sense!)
Please flag errorsToday or [email protected]
Number of outstanding issuesOverlap with outcomes from UKNEQAS UV pilot scheme
2012
TODAYComing togetherReach consensusRecommendations 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)
2013 DRAFT guidelines-what next?
4.2 Presence or absence on SNP DatabasesSection promoted and extendedAdditional informationUseful/accurate/problems?What rules do labs use to assign benign
polymorphism?
4.5 Co-segregation with the disease in the familyInclusion 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 conservationSignificantly expanded
Lots of new referencesDoes 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 effectSignificant 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 predictionSignificantly expandedAdditional references includedAlamut 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 variantsNumber of outstanding issues related4 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
What’s new and requires further discussion in v2?
Final ThoughtsLots 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
AcknowledgementsParticipants attended the follow up BP
meeting 2011Kathryn RobertsonAndrew DevereauStewart PayneCiaron McAnultyDutch lab colleagues