1. Somatic-to-germline testing pathways
Breakout session 1
Somatic-to-germline testing pathways

2. Format Round table discussion
5 working groups – Breast, Colorectal, Ovarian, Other, TP53
Three documents on table
Individual variant testing scoring form (all to complete)
Individual table specific scoring form (all to complete)
Table specific collated comments form (table scribe to complete on behalf of table)
Forms should be completed after round table discussion of the questions on the forms

3. Working groups Facilitator/scribe
Breast
Colorectal
Ovarian*
Other
TP53
Anju Kulkarni
Julian Barwell
Mary Porteus
Fiona Lalloo
Angie Brady
Jackie Cook
Julian Adlard
Katie Snape
Clare Turnbull
Helen Hanson
Marc Tischkowitz
Paul Brennan
Alex Murray
Shirley Henderson
Ellen Thomas
Carole Brewer
Gail Norbury
Athalie Melville
Mikel Valganon
Jane Chalker
Kai-Ren Ong
Amy Taylor
Yvonne Wallis
Vishakha Tripathi
Julia Finch
Andrew Wallace
Nirupa Murugaesu
Angela George
Angela Hamblin
Patrick Tarpey
Kelly Kohut
Michael Braun
Ranjit Manchandra
Mark Davies
Rosemarie Davidson
Ellen Copson
Ian Frayling
Alan Donaldson
Dorothy Halliday
Zoe Kemp
Muna Ahmed
Ray McMahon
Claire Searle
Zosia Miedzybrodzka
Facilitator/scribe
* Plus additional two Astra Zeneca delegates (Patrick Fivey and Robert Armour)

4. Tumour-specific genes
Breast
BRCA1, BRCA2, PALB2, (CHEK2, ATM, BARD1, NBN)
Bowel
BMPR1A, MLH1, MSH2, MSH6, MUTYH,  PMS2, (APC, POLD1, POLE)
Ovarian
BRCA1, BRCA2, MLH1, MSH2, MSH6, RAD51C, RAD51D, BRIP1
Other
RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TSC2, VHL, FH, FLCN, BAP1
TSC1 was not present in the data but could be considered alongside TSC2

5. Individual variant testing scoring form (1)
After discussion on your table, please rank the following statements from 1 -5 where 1 is strongly disagree and 5 is strongly agree
strongly disagree disagree neutral agree strongly agree
If a somatic variant is identified, germline testing should be undertaken in the following situations:
Only for class 4/5 variants
Only if there is a ≥10% likelihood of detecting a germline mutation
For intermediate penetrance variants in known high penetrance genes
Only where there is strong evidence for cancer susceptibility (e.g. not BARD1, NBN)
In intermediate penetrance genes (e.g. CHEK2, ATM)

6. Individual variant testing scoring form (2)
After discussion on your table, please rank the following statements from 1 -5 where 1 is strongly disagree and 5 is strongly agree
strongly disagree disagree neutral agree strongly agree
If a somatic variant is identified, germline testing should be undertaken in the following situations:
Where there is a ≥10% likelihood of detecting a germline mutation in an "on-tumour" setting
Where there is a ≥10% likelihood of detecting a germline mutation in an "off-tumour" setting for all genes
Where there is a ≥10% likelihood of detecting a germline mutation in an "off-tumour" setting for genes on the ACMG secondary finding list
Where there is a ≥10% likelihood of detecting a germline mutation in an "off-tumour" setting for all genes for which there are agreed UK clinical management guidelines for germline mutation carriers
Where there is a <10% likelihood of detecting a germline mutation in an "on-tumour" setting

7. Table specific individual forms
Consider whether you would support germline testing for your table specific genes in the following situations:
On-tumour = variant identified in tumour type for which there is clear evidence of association with the gene in question in a hereditary setting
Akin to diagnostic test
e.g. BRCA1 in breast cancer
Off-tumour = variant identified in tumour type for which there is no or limited evidence of association with the gene in question in a hereditary setting
Akin to secondary finding
e.g. BRCA1 in colorectal cancer
Consider response under current resource and if this would change if additional resource was available

8. Table specific individual forms
Data suggest 10% threshold is reached irrespective of whether variant identified in On- or Off-tumour setting for:
BMPR1A, BRCA1, BRCA2, BRIP1, MLH1, MSH2, MSH6, MUTYH, PALB2, PMS2, RAD51C, RAD51D, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TSC2, VHL (except in RCC)
Data suggest 10% threshold is only reached when variant is identified in On-tumour setting for:
FH, FLCN, BAP1 - though note numbers are small
‘Other’ genes table: consider whether germline testing should only be offered for genes which meet ACMG criteria or extend to all CPGs for which there is recognised clinical management in the UK?
TP53 table- Data suggest 10% threshold is only reached for specific variants

9. TP53 - variant-specific gene
As TP53 is so frequently mutated somatically in sporadic cancers, data suggests that only specific variants currently meet the 10% likelihood threshold.
If a somatic variant is identified, germline testing should be undertaken in the following situations:
with current resources
with unlimited resources
In all tumour types where data suggests that the identified variant meets ≥ 10% threshold
In all tumour types even if the identified variant does not meet the ≥ 10% threshold
Only in strongly associated tumour types (e.g. classic LFS syndrome cancers) where data suggests that the identified variant meets ≥ 10% threshold
In strongly associated tumour types (e.g. classic LFS syndrome cancers) even if data does not suggest that the identified variant meets the ≥ 10% threshold
In all breast cancers even if the identified variant does not meet ≥ 10% threshold
In all tumour types where data suggests that the identified variant meets ≥ 10% threshold only when age thresholds are applied e.g. all patients under 50

10. Collated comments form
Should age thresholds be required in addition to the somatic variant data prior to germline testing?
If so, what would you pragmatically recommend they should be?
Are there situations in which referral for additional assessment should be recommended prior to germline testing? ( e.g. family history assessment)
Are there any other cancer types you would consider to be "on-tumour" associations with any of the genes discussed on your table?
Other discussion points

11. Consent and clinical pathways
Breakout session 2
Consent and clinical pathways

12. Format Round table discussion 2 sections Consent (25 minutes)
Schematic of patient’s clinical journey x2
WGS pathway – paired tumour and germline samples taken at point of diagnosis
NGS panel pathway – usually tumour sample only taken at point of diagnosis and germline sample acquired at a later time point if needed
Clinical pathways (25 minutes)
Flowchart of proposed clinical pathways
Scribe to annotate schematics/flowchart with outcome of discussion and document any additional points in notepad on behalf of table

13. Consent
Should patients be "obliged" to receive germline results if they are having a somatic test for the purposes of cancer management?
For both WGS and NGS panels in On- and Off-tumour settings:
When should generic consent for germline susceptibility testing take place?
Who should obtain this consent?
To what depth should this consent be taken?
When should discussion regarding validation of a potential germline variant +/- acquisition of germline sample take place?
Which clinician should have that discussion with the patient?
Who should convey validated germline results to the patient?
Should consent pathways differ by gene/tumour type?
How should consent be obtained for childhood tumours where majority of potential germline findings will be Off-tumour with adult-onset implications?

14. Result-giving: somatic +/- germline
Patients approached regarding consent for data usage (inc genomic tests) early in clinical journey
Generic information
Investigatory Procedure: obtain samples
Histopathology: confirms cancer
Result-giving: somatic +/- germline
Molecular tests
Data Analysis +
Information/choices (germline testing)
Information/choices (research)
Information
/choices (secondary findings)

15. Clinical pathways
Taking into account both On- and Off-tumour settings:
What should be the roles of oncology and inherited cancer services?
How ideally (resource-dependent) should referrals between the services work?
Do you broadly agree with the proposed clinical pathway?
If not, what are your concerns and what changes would you make?
What challenges do you envisage in implementing these pathways locally?
What additional resources would be required for implementation?
How should we manage referrals from private and direct-to-consumer sources?

16. Molecular tumour board Tumour-specific MDT
Feedback actionable somatic/germline variants to Tumour MDT
Request Genomic Laboratory to perform reflex validation of On-tumour germline variants if informed consent in place
Advise Tumour MDT to refer Off-tumour and non-consented On-tumour germline variants to Clinical Genetics prior to validation
Tumour-specific MDT
Feedback consented On-tumour germline results to patient and refer onwards to Clinical Genetics
Refer Off-tumour and non-consented On-tumour germline variants to Clinical Genetics for informed consent prior to validation
Refer On- and Off-tumour germline variants to Clinical Genetics for further management if patient deceased
NGS panel/WGS of tumour
Genomic Laboratory
Reflex validation of On-tumour germline variants at request of Molecular Tumour Board
Validation of On- and Off-tumour germline variants at request of Clinical Genetics
Consent for actionable somatic mutations +/- On- +/- Off-tumour germline susceptibility
New symptomatic patient
Diagnostic tissue biopsy sample plus blood sample to store lymphocytic DNA
Primary and Secondary care
Clinical Genetics Service
Obtain informed consent for validation of Off-tumour and non-consented On-tumour germline variants
Ensure germline testing offered as per NHSE rare disease and cancer test directory
Make recommendations for management of patient’s future cancer risks
Institute cascade predictive testing for family members
Patient with previous personal +/- family history (FH) cancer
Digital FH questionnaire
Cancer Genetics app
FH risk assessment clinics
Personal and family history assessment