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

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

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)

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

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 1 2 3 4 5 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)

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 1 2 3 4 5 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

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

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

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

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

Consent and clinical pathways Breakout session 2 Consent and clinical pathways

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

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?

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)

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?

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