1. Variant Triaging and ESMO Guidelines
Chris Wragg

2. Chris Wragg Cancer Validation and Reporting Meeting, 7th November 2018
Variant Triaging
Chris Wragg
Cancer Validation and Reporting Meeting,
7th November 2018

3. Introduction Increase in diagnostic somatic NGS
Test directory requires expanded Cancer NGS Panels
Analysis of 100k genome results
Discrepancies between labs in how variants are classified and reported
Majority use 5 Class system (ACMG)
Not suitable for somatic variants
Li et al (2017)

4. Standardisation
Rare disease classification has been standardised through adopting the ACMG guidelines
Workshops established (scientist + clinician)
Monthly WebEx
Disease specific working groups e.g. C-VIG
Data sharing

5. Somatic

6. Actionability
A variant can be considered a biomarker that affects clinical care (clinically actionable) if it:
Predicts sensitivity, resistance, or toxicity to a specific therapy
Alters the function of the gene which can be targeted by approved investigational drugs
Serves as an inclusion criterion for clinical trials
Influences disease prognosis
Assists in establishing a diagnosis of a cancer
Warrants implementing surveillance measures for early cancer detection
Li et al. The Journal of Molecular Diagnostics, Vol. 19, No. 1, January 2017
Section Cancer Validation and Reporting Guidelines

7. UK Somatic Variant Interpretation Group
Stakeholders from across Cancer Clinical and Diagnostic Community aiming to:
Establish current practice
Identify and share good practice
Standardise assessment of pathogeneticity/actionability
Develop/adopt national SVI guidance
Mainstreaming/Education

8. UK-SVI Workshop 21st September 2018, Birmingham
EQA scheme experience of SVI (GenQA, UKNEQAS LI)
Competency schemes (G-TACT)
How to establish pathogenicity
How to establish actionability
Results of practice variant classification
Lightning presentations capturing current practice
Focussed discussion

9. UK-SVI Workshop Working groups established: Pathogenicity
Actionability
Germline findings
Reporting

10. UK-SVI: Pathogenicity
Current practice:
Predict functional consequences (literature, in silico predictions)
Mechanism of activity (activate oncogene/inactivate TS)
Population databases
Cancer specific databases
Driver annotation:
Establish resources/databases
Train classifiers
Validate

11. UK-SVI: Actionability
Paper
Definition
Therapy
Investigational
Prognosis /Diagnosis
Hypothetical Target
Germline therapy
Germline Risk
Van Allen (2013) ✔
Meric-Bernstam (2015)
Sukhai (2016)
Li (2017)
Mateo (2018)

12. UK-SVI: Actionability
Guidelines agree on what should be used to determine actionability
Actionability determined through assessment of:
Known associated therapies / prognostic or diagnostic implications
Clinical trial results
Eligibility criteria for a clinical trial
Preclinical data for response to therapy / association with prognosis or diagnosis
Literature
Guidelines differ on how the evidence is used – weighting of evidence and classification framework

13. UK-SVI: Next Steps Working groups established and ToR being defined
Aligning with parallel projects e.g. from CRUK (SMP2)
Seeking expanded involvement to include more Oncologists/Haematologists
Aim to produce harmonised UK Somatic Variant Interpretation recommendations
Best practice guidance for somatic bioinformatic pipelines being developed
Data sharing opportunities under review
Education/Training/Mainstreaming