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

1 st Best Practice Guidelines

January 2008

Interpretation & Reporting of UVs

Draft Updated Guidelines

February 2013

Interpretation & Reporting of Rare & Novel Variants

UKNEQAS UV Participants Workshop

March 2013

Follow up Best Practice Meeting

March 2011 Birmingham CMGS labs

Pathogenicity of sequence variants interpretation

Pilot EQA scheme 2012

Final Updated Guidelines

March 2013

Interpretation & Reporting of Rare & Novel Variants

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 [email protected]

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  1 st 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