Pertinent Germline Findings Clare Turnbull

Pertinent Germline Findings: 100K and GMS Clare Turnbull V&R meeting 6/11/18

Pertinent Germline Findings on WGS analysis

Virtual Gene Panels for each cancer type Tumour Type Virtual Gene Panels for each cancer type Breast cancer BRCA1, BRCA2, PALB2, PTEN, TP53, ATM, CHEK2 Colorectal cancer MLH1, MSH2, MSH6, MUTYH (bi), PMS2, POLD1, POLE, PTEN, SMAD4, STK11 Ovarian cancer BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, RAD51C, RAD51D Prostate cancer BRCA2 Renal Cancer FH, FLCN, PTEN, SDHB, VHL, MET Sarcoma TP53, expanded Melanoma BAP1, CDK4, CDKN2A Endometrial cancer FH, MLH1, MSH2, MSH6, PMS2, PTEN Adult Glioma APC, ATM (bi), MLH1, MSH2, MSH6, PMS2, TP53 Head and Neck BRIP1 FANCA FANCB FANCC FANCD2 FANCE FANCF FANCG FANCI FANCL FANCM Neuroendocrine CDKN1B, MAX, MEN1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, FH, VHL Thyroid RET, PTEN, CDKN1B Upper GI MLH1, MSH2, MSH6, PMS2 Frequency: 2-3%

Germline analysis: tier 3 variants in cancer susceptibility genes 17 February 2019 Germline analysis: tier 3 variants in cancer susceptibility genes Tier 1 On-tumour associations only Truncating variants in LOF genes (unless benign/likely benign with two stars in ClinVar) AND Pathogenic/likely pathogenic with two stars in ClinVar Tier3 Broad panel of genes that confer susceptibility to cancer Non-synonymous variants < 0.5% MAF for AD < 2% MAF for AR Internal Genomics England freq NOT benign/likely benign with ≥two stars in ClinVar

Tier 3 panels Haem Onc Child Adult 17 February 2019 Tier 3 panels Haem Onc Adult Child APC EPCAM PALB2 SDHB ATM FH PMS2 SDHC BAP1 FLCN POLD1 SDHD BMPR1A KIT POLE SMAD4 BRCA1 MAX PTCH1 SMARCA4 BRCA2 MEN1 PTEN SMARCB1 BRIP1 MET RAD51C STK11 CDC73 MLH1 RAD51D SUFU CDH1 MSH2 RB1 TMEM127 CDK4 MSH6 RET TP53 CDKN1B MUTYH SDHA TSC1 CDKN2A NF1 SDHAF2 TSC2 DICER1 NF2 VHL CHEK2 NTHL1 WT1 ALK ERCC5 NF1 SHOC2 APC FANCA NF2 SMAD4 ATM FANCC NHP2 SMARCA4 BLM FANCD2 NOP10 SMARCB1 BMPR1A FANCE NRAS SOS1 BRAF FANCF PALB2 STK11 BRCA1 FANCG PAX5 SUFU BRCA2 FANCI PHOX2B TERT BRIP1 FANCL PMS2 TP53 CBL HRAS PRKAR1A TSC1 CDKN1C KRAS PTCH1 TSC2 DDB2 MAP2K1 PTEN VHL DICER1 MAP2K2 PTPN11 WRN ERCC1 MEN1 RAF1 WT1 ERCC2 MLH1 RB1 XPA ERCC3 MSH2 RECQL4 XPC ERCC4 MSH6 RET FANCM NBN RAD51C ACD FANCF PMS2 RPS29 ANKRD26 FANCG PRF1 RPS7 ATM FANCI PTPN11 RTEL1 BLM FANCL RPL11 RUNX1 BRCA1 FAS RPL15 SAMD9L BRCA2 GATA1 RPL23 SBDS BRIP1 GATA2 RPL26 SH2D1A CBL GBA RPL27 SLX4 CEBPA HAX1 RPL31 STAT3 CTC1 ITK RPL35A STN1 DDX41 LIG4 RPL36 TERT DKC1 MAD2L2 RPL5 TINF2 DOCK8 MLH1 RPS10 TP53 ELANE MSH2 RPS15 TSR2 ERCC4 MSH6 RPS17 UBE2T ETV6 NAF1 RPS19 WAS FANCA NBN RPS24 WRAP53 FANCB NF1 RPS26 XRCC2 FANCC NHP2 RPS27 RMRP FANCD2 NOP10 RPS27A TERC FANCE PALB2 RPS28 FANCM PARN RAD51 PAX5 RAD51C SH2B3 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)

Germline analysis: New report format 17 February 2019 Germline analysis: New report format

Germline analysis: New report format 17 February 2019 Germline analysis: New report format

Current 100K WGS vs Future GLS WGS Tier 3 variants: Current scenario: WGS within 100KGP Research project Optional for lab to review Tier 3 Value: Contain additional vars for genes on panels (weaker evidence than 2 stars in ClinVar) Contain additional vars that may be indicated by family history rather than specific tumour type Future scenario: WGS within GMS Review of tier 3: ?optional Issues around consent: some will be secondary findings Standards: ?sufficient as equivalent to germline test

Adaptations to Cancer WGS analysis for GMS Expansion of variants included in Tier 1 All ClinVar LP/P+ conflicting (if ≤ 1 benign and ≥pathogenic) Flags (eg near 3’ end on gene) QC metrics (% gene covered at depth/sensitivity) CNV reporting (issues: confidence of calls vs prior of true positive)

Findings on tumour-only analysis of potential germline origin

PREMLINARY ANALYSIS

Inherited Cancer in Rare Disease Testing Directory

‘Inherited’ Cancer Testing Indications

Tumour testing for For deceased individual: For diagnostic pathway BRCA1/BRCA2 Lynch CDH1 Other For diagnostic pathway Lynch (demonstrate biallelic somatic mutations)

Feedback received This section needs to be updated to take into account the relaxation of the type of germline variants in cancer susceptibility genes which no longer need to have 2* in ClinVar. Can consideration be given to return of germline variants associated with drug metabolism used in cancer treatment e.g. DPYD variants and 5FU in CRC?