Cancer Validation and Reporting Guidance Update 4th June 2016

Guidance for the Validation and Reporting of Whole Genome Sequencing Results for the 100,000 Genomes Project Cancer Programme v1.15 June 2018 Contributors: Mary Alikian, Sandi Deans, Salvador Diaz-Cano, Helen Dickenson, Angela Hamblin, Shirley Henderson, Sandra Hing, Jane Moorhead, Emily Shaw, Graham Taylor, Clare Turnbull, Andrew Wallace, Nick West and Chris Wragg  

Main Changes Inclusion of contributors on behalf of the working group Section 2.2: Inclusion of comment regarding the flagging of low level variants by Genomics England. Section 3.1.4: Inclusion of reporting of germline findings for deceased patients. Section 4.7 Inclusion of NHS GMC reviewed but unvalidated variants in GTAB summary. Amendment of GTAB outcome summary form to reflect this Deletion of some sections of appendix 5 as replaced by clinical report in appendices 10 and 11 (?9/10). Deletion of appendix 7 (‘no actionable findings letter’) as replaced by clinical report in appendix 9. Inclusion of flow chart for WGS analysis process to summarise the pathway.

This guidance will evolve as more results are returned to the NHS GMCs therefore we envisage frequent reviews and updates will follow.

Section 2.2: Flagging of low level variants by Genomics England. Three new three flags are to be introduced by Genomics England: A variant with a germline allele frequency > 1% in an internal Genomics England data set (indicates potential un-subtracted germline variant) A recurrently identified somatic variant with somatic allele frequency > 5% in an internal Genomics England data set (indicates potential technical artefact) A variant overlapping simple repeats A notification will be issued when these have been introduced.

Section 3.1.4: Reporting of germline findings for deceased patients However, if a germline variant has been identified in a deceased patient this shall be validated due to familial implications and if confirmed then reported to the referring clinician (Appendix 1 – WGA Workflow)

Section 4.7 Inclusion of unvalidated variants in GTAB summary It is important for patient safety that clinical decisions are not influenced by unvalidated WGS findings. Therefore if a decision is made to include the output documentation from the GTAB discussion (which contains unvalidated findings) in a  patient’s paper notes or electronic patient record (EPR) then a  very clear statement that unvalidated findings shall not be acted upon must be included. 

Section 4.7 Inclusion of unvalidated variants in GTAB summary  In the event of a change in clinical circumstances the treating clinician shall contact and discuss with relevant healthcare professionals if validation is now deemed appropriate and arrange for technical validation to be performed on the specified variant before any clinical action is taken. This shall be further documented on a GTAB outcome form.  

GENOMICS ENGLAND PARTICIPANT INFORMATION PLEASE NOTE THAT ALL VARIANTS MUST BE VALIDATED BY THE LABORATORY PRIOR TO CLINICAL DECISIONS BEING TAKEN. THE DATA DISCUSSED MAY INCLUDE UNVALIDATED FINDINGS WHICH MUST NOT BE ACTED UPON. PLEASE CONTACT THE LABORATORY TO DISCUSS. GENOMICS ENGLAND PARTICIPANT INFORMATION Patient Name GEL Participant ID Gender   NHS Number DoB Hospital Number Referring clinician Referring Hospital SAMPLE INFORMATION Tumour Type and Subtype   WHOLE GENOME ANALYSIS (WGA) Date issued WGA version number GTAB SUMMARY and Date: CLINICAL UPDATE: Include any SOC testing already performed WGA SOMATIC FINDINGS: Suggest listing gene name/s and allele frequency with a comment regarding contacting laboratory for variant level detail   ADDITIONAL FINDINGS (including Cancer Pertinent Germline Susceptibility): CONCLUSIONS (Including actions and owners):

Appendix 1: WGA Workflow Is Patient Alive? Is Patient undergoing active management for cancer? GTAB meeting WGS variant review of tiers 1, 2 and 3 somatic variants - tiering for clinical actionability and outcome. Review of pertinent germline findings. Record all outcomes on GTAB summary form. Review of WGS required. Flag on EPR that WGS performed and document variant review. To be reviewed if/when clinically required Re analysis of whole genome data MDT meeting Review of actionable variants, acquired and germline *Technical Validation to be undertaken for any variant being ‘actioned’ i.e. to be used for managing current clinical situation Clinical Reporting Technical Validation of pertinent germline findings to be undertaken if required No Yes No review of somatic WGS required but review of pertinent germline findings required Relapse/Recurrence/Other Optional Review of supplementary report No

Appendices 9 and 10: Cancer Genomic Reports Deletion of some sections of appendix 5 as replaced by clinical report in appendices 9 and 10. Deletion of appendix 7 (‘no actionable findings letter’) as replaced by clinical report in appendix 9.

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