Pertinent Germline Findings and Additional Secondary findings Clare

Pertinent Germline Findings and Additional (Secondary) findings Clare Turnbull NHSE V&R group 5/6/18

Pertinent Germline Findings

Tumour Type Genes analysed Breast cancer Colorectal cancer BRCA 1, BRCA 2, PALB 2, PTEN, TP 53 MLH 1, MSH 2, MSH 6, MUTYH (bi), PMS 2, POLD 1, POLE, PTEN, SMAD 4, STK 11 BRCA 1, BRCA 2, MLH 1, MSH 2, MSH 6, PMS 2, RAD 51 C, RAD 51 D BRCA 2 FH, FLCN, PTEN, SDHB, VHL, MET TP 53, expanded BAP 1, (CDK 4), CDKN 2 A FH, MLH 1, MSH 2, MSH 6, PMS 2, PTEN Ovarian cancer Prostate cancer Renal Cancer Sarcoma Melanoma Endometrial cancer Adult Glioma Head and Neck Neuroendocrine Thyroid Upper GI APC, ATM (bi), MLH 1, MSH 2, MSH 6, PMS 2, TP 53 BRIP 1 FANCA FANCB FANCC FANCD 2 FANCE FANCF FANCG FANCI FANCL FANCM CDKN 1 B, MAX, MEN 1, RET, SDHAF 2, SDHB, SDHC, SDHD, TMEM 127, FH, VHL RET, PTEN, CDKN 1 B MLH 1, MSH 2, MSH 6, PMS 2 Tier 1 • Only vars are reported which are (a) truncating AND/OR (b) 2* on Clinvar as likely pathogenic/pat hogenic • Larger germline panels • haem-onc, • childhood, • adult solid tumours • No panel for lung, TGCT, bladder • All panels are on Panel. App for review, appraisal Frequency: 9/360= 2 -3% 3

Published series • 1) Jones et al (Velculescu), Sci Transl Med, 2015 -815 patients, 15 common (adult) tumour types -85 cancer susceptibility genes -mutations in 27/815 (3%) 2) Bryce et al (Berg), Clin Cancer Res. , 2016 - 439 patients, 10 common (adult) tumour types - 36 cancer susceptibility genes - mutations in 19/439 (4. 3%), 12/439 ‘concordant’ (2. 7%) (incl 4 CHEK 2, ATM) - -mutations in 8/439 by our pertinent gene list (1. 8%) 4

TCGA Germline analysis Adult cancers: TCGA: Lu et al, Nat Comms, 2015 • 4034 cases from TCGA • 12 cancer types • 114 cancer susceptibility genes+ 47 DNA repair genes • No matching for pertinence • Intermediate penetrance genes (ATM, ATR, CHEK 2, BARD 1, BRIP 1) • Monoallelic mutations for biallelic conditions (Mut. YH, XPC)

Additional germline reporting: Tier 3 a variants • “Tier 3 a” variants: Additional germline variants in large set of cancer susceptibility genes • ADULT SOLID: full adult solid+ childhood solid panel • ADULT HAEMONC: full adult solid panel+childhood solid+haem-onc panel • CHILDHOOD: childhood solid+haem-onc • MAF< 0. 5% (AD), MAF<2% (AR) • Display of germline findings in VI: Q 3 2018 • “Tier 3 b” variants: Additional germline variants in genes of potential therapeutic relevance • germline vars of MAF<1% • CGC list: 560 genes (large set of genes relating to cancer development/ oncogenesis) • Annotate by clinical trials 6

Additional (Secondary) Findings

ACMG: 25 Cancer Susceptibility Genes (2016) Phenotype Gene Hereditary Breast and Ovarian Cancer BRCA 1 RET Li-Fraumeni Syndrome TP 53 Multiple Endocrine Neoplasia Type 2, Familial Medullary Thyroid Cancer (FMTC) Peutz-Jeghers Syndrome Lynch Syndrome BRCA 2 STK 11 PTEN Hamartoma Tumor Syndrome PTEN MLH 1 Retinoblastoma RB 1 MSH 2 MSH 6 PMS 2 SDHD SDHAF 2 Hereditary Paraganglioma- Pheochromocytoma Syndrome SDHC Familial adenomatous polyposis APC SDHB MYH-Associated Polyposis MUTYH Von Hippel Lindau syndrome VHL Tuberous Sclerosis Complex TSC 1 Multiple Endocrine Neoplasia Type 1 MEN 1 WT 1 -related Wilms tumor WT 1 Neurofibromatosis type 2 NF 2 Juvenile polyposis syndrome, BMPR 1 A Juvenile polyposis syndrome SMAD 4 8 TSC 2

ACMG: 25 Cancer Susceptibility Genes (2016) Phenotype Gene Hereditary Breast and Ovarian Cancer BRCA 1 RET Li-Fraumeni Syndrome TP 53 Multiple Endocrine Neoplasia Type 2, Familial Medullary Thyroid Cancer (FMTC) Peutz-Jeghers Syndrome Lynch Syndrome BRCA 2 STK 11 PTEN Hamartoma Tumor Syndrome PTEN MLH 1 Retinoblastoma RB 1 MSH 2 MSH 6 PMS 2 SDHD SDHAF 2 Hereditary Paraganglioma- Pheochromocytoma Syndrome SDHC Familial adenomatous polyposis APC SDHB MYH-Associated Polyposis MUTYH Von Hippel Lindau syndrome VHL Tuberous Sclerosis Complex TSC 1 Multiple Endocrine Neoplasia Type 1 MEN 1 WT 1 -related Wilms tumor WT 1 Neurofibromatosis type 2 NF 2 Juvenile polyposis syndrome, BMPR 1 A Juvenile polyposis syndrome SMAD 4 9 TSC 2

Aortic aneurysm, familial thoracic MYH 11 Left ventricular noncompaction Loeys-Dietz syndrome TNNT 2 ACTA 2 TMEM 43 DSP PKP 2 DSG 2 Long QT syndrome DSC 2 TGFBR 1 TGFBR 2 Brugada syndrome 1 Catecholaminergic polymorphic ventricular tachycardia SCN 5 A RYR 2 KCNH 2 SCN 5 A Dilated cardiomyopathy LMNA MYBPC 3 COL 3 A 1 Arrhythmogenic right ventricular cardiomyopathy Ehlers-Danlos syndrome, type 4 Fabry's disease Familial hypercholesterolemia OCT deficiency Wilson disease GLA APOB LDLR PCSK 9 OTC ATP 7 B Malignant hyperthermia Marfan's syndrome Familial hypertrophic cardiomyopathy SMAD 3 KCNQ 1 ACMG: 34 Non -Cancer Susceptibility (2016) RYR 1 CACNA 1 S FBN 1 TGFBR 1 MYH 7 TPM 1 MYBPC 3 PRKAG 2 TNNI 3 MYL 2 ACTC 1 10

Aortic aneurysm, familial thoracic MYH 11 Left ventricular noncompaction Loeys-Dietz syndrome TNNT 2 ACTA 2 TMEM 43 DSP PKP 2 DSG 2 Long QT syndrome DSC 2 TGFBR 1 TGFBR 2 Brugada syndrome 1 Catecholaminergic polymorphic ventricular tachycardia SCN 5 A RYR 2 KCNH 2 SCN 5 A Dilated cardiomyopathy LMNA MYBPC 3 COL 3 A 1 Arrhythmogenic right ventricular cardiomyopathy Ehlers-Danlos syndrome, type 4 Fabry's disease Familial hypercholesterolemia OCT deficiency Wilson disease GLA APOB LDLR PCSK 9 OTC ATP 7 B Malignant hyperthermia Marfan's syndrome Familial hypertrophic cardiomyopathy SMAD 3 KCNQ 1 ACMG: 34 Non -Cancer Susceptibility (2016) (29/5) RYR 1 CACNA 1 S FBN 1 TGFBR 1 MYH 7 TPM 1 MYBPC 3 PRKAG 2 TNNI 3 MYL 2 ACTC 1 11

Timeline • Preliminary analysis underway on test dataset • Pipeline analysis • Loss-of-function • Clin. Var (high confidence) • Curated lists: ATA (RET), LOVDs (LDLR) • Gene specific rules (eg PCSK 9) • Consent analysis • Additional/reproductive • Adult/Childhood • Predicted frequency in general population for gene set of 13 genes ~1% • Lower frequency for cancer program • Lower consent rate • Already reported as pertinent • Local review of variants and technical validation required • Delivery planned for Nov 2018 12

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