ClinGen: The Clinical Genome Resource - Heidi Rehm

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Recently, three NIH-funded efforts were aligned with the National Center for Biotechnology Information’s (NCBI) ClinVar database under the collaborative Clinical Genome Resource Program (ClinGen - http://www.iccg.org/about-the-iccg/clingen). ClinGen is developing interconnected resources for the community to improve our understanding of genomic variation and optimize its use in genomic medicine. A unique aspect of ClinGen is that it represents a strong public-academic-private partnership that relies on the collaboration between NIH, academic and commercial genetic testing laboratories. The project includes the development of standards for variant interpretation as well as data submission and sharing. ClinVar, launched in April 2013, is a cornerstone of the project as it serves as the primary site for deposition and retrieval of variant data and annotations. As of February 1st, 2014 ClinVar contains 73,487 submissions across 18,702 genes (66,956 unique variants) with interpretations from OMIM, GeneReviews, 60 laboratories, and 23 locus-specific databases (LSDBs). The dataset includes 5454 variant submissions (2095 unique variants) from the Sharing Clinical Reports Project (SCRP - http://sharingclinicalreports.org) on BRCA1/2 and 4100 copy number variants from the International Standards for Cytogenomic Arrays consortium. New policies and data structures are being considered to support controlled access to patient-level data. ClinGen is currently working with many laboratories and LSDBs to support robust mechanisms to share their data in an ongoing manner and increase the content of structured data and supporting evidence. Other parts of the project include computational and machine-learning approaches for identifying clinically relevant variants, and the development of expert working groups across many clinical domains to support consensus-driven evidence-based curation of genes-disease associations and genomic variant interpretations. Groups have already been formed in the areas of cardiovascular disease, hereditary cancer, metabolic disease, rasopathies, congenital muscular dystrophy, and developmental delay. The project is also interfacing with a large and diverse community of stakeholders including professional organizations, patient advocacy groups, regulatory agencies, research consortia and other projects from both national and international sites which is facilitated by working with the existing International Collaboration for Clinical Genomics (ICCG - http://www.iccg.org). This talk will give an overview of the ClinGen resource and progress made to date.

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ClinGen: The Clinical Genome Resource - Heidi Rehm

  1. 1. Heidi L. Rehm, PhD Partners Healthcare and Harvard Medical School ClinGen Clinical Genome Resource
  2. 2. The Problem > 100 million genomic variants in humans >20,000 genes Most we don’t understand
  3. 3. 0 200 400 600 800 1000 1200 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 0 2 4 6 8 10 12 14 16 18 20 Lung Cancer KRAS EGFR G12C L858R GJB2 35delG GJB2 M34T PTPN11 N308D MYBPC3 R502W 68% of pathogenic/ likely pathogenic variants are seen only once 96% of variants are seen <10 times Number of Probands NumberofVariantsHistogram of Pathogenic Variants from Diagnostic Testing of 15,000 Probands (cardiomyopathy, hearing loss, rasopathies, aortopathies, somatic and hereditary cancer pulmonary disorders, skin disorders, other genetic syndromes) 31% VUS 25% Positive 61% Negative 14% Inconclusivenclusive 52% Benign 17% Path
  4. 4. Clinical Domain WGs Chairs: Jonathan Berg & Sharon Plon Cancer co-chairs: Matthew Ferber, Ken Offit, Sharon Plon Cardiovascular co- chairs: Euan Ashley, Birgit Funke, Ray Hershberger Metabolic co-chairs: Rong Mao, Robert Steiner, David Valle Pharmacogenomic co- chairs: Teri Klein, Howard McLeod ClinGen Working Groups (WG)ClinGen Working Groups (WG) Actionability WG Chair: Jim Evans Informatics WG Chair: Carlos Bustamante EHR WG Chair: Marc Williams ClinVar IT Standards and Data Submission WG Chairs: Sandy Aronson & Karen Eilbeck Gene Curation WG Chairs: Jonathan Berg & Christa Martin Sequence Variant WG Chairs: Sherri Bale, Heidi Rehm, & Madhuri Hegde Structural Variant WG Chairs: Swaroop Arahdya & Erik Thorland ELSI and Genetic Counseling WG Chair: Andy Faucett & Kelly Ormond Education, Engagement, Access WG Chair: Andy Faucett Phenotyping WG Chair: David Miller ClinGen The Clinical Genome Resource Launched Sept 2013 NCBI ClinVar Leads Melissa Landrum Jennifer Lee Donna Maglott George Riley Steve Sherry U41 Grant PIs David Ledbetter Christa Martin Bob Nussbaum Heidi Rehm U01 PIs Jonathan Berg Jim Evans David Ledbetter Mike Watson U01 PIs Carlos Bustamante Sharon Plon NHGRI Program Directors Lisa Brooks Erin Ramos ClinVar vs. ClinGen? • ClinVar is a database • ClinGen, The Clinical Genome Resource, is an NIH funded program supporting a wide range of activities encompassing both support for ClinVar (funded through NCBI) as well as other projects • ClinGen includes 3 grants primarily funded by the National Human Genome Research Institute at NIH
  5. 5. Clinical Domain WGs Chairs: Jonathan Berg & Sharon Plon Cancer co-chairs: Matthew Ferber, Ken Offit, Sharon Plon Cardiovascular co- chairs: Euan Ashley, Birgit Funke, Ray Hershberger Metabolic co-chairs: Rong Mao, Robert Steiner, David Valle Pharmacogenomic co- chairs: Teri Klein, Howard McLeod ClinGen Working Groups (WG)ClinGen Working Groups (WG) Actionability WG Chair: Jim Evans Informatics WG Chair: Carlos Bustamante EHR WG Chair: Marc Williams ClinVar IT Standards and Data Submission WG Chairs: Sandy Aronson & Karen Eilbeck Gene Curation WG Chairs: Jonathan Berg & Christa Martin Sequence Variant WG Chairs: Sherri Bale, Heidi Rehm, & Madhuri Hegde Structural Variant WG Chairs: Swaroop Arahdya & Erik Thorland ELSI and Genetic Counseling WG Chair: Andy Faucett & Kelly Ormond Education, Engagement, Access WG Chair: Andy Faucett Phenotyping WG Chair: David Miller ClinGen The Clinical Genome Resource Launched Sept 2013 NCBI ClinVar Leads Melissa Landrum Jennifer Lee Donna Maglott George Riley Steve Sherry U41 Grant PIs David Ledbetter Christa Martin Bob Nussbaum Heidi Rehm U01 PIs Jonathan Berg Jim Evans David Ledbetter Mike Watson U01 PIs Carlos Bustamante Sharon Plon NHGRI Program Directors Lisa Brooks Erin Ramos
  6. 6. Goals of ClinGen To raise the quality of patient care by: • Standardizing the annotation and interpretation of genomic variants • Sharing variant and case level data through a centralized database for clinical and research use • Developing machine-learning algorithms to improve the throughput of variant interpretation • Implementing an evidence-based expert consensus process for curating genes and variants • Assessing the actionability of genes and variants and supporting their use in clinical care systems
  7. 7. Public LSDBs >600 Pharm GKB Population Databases EVS 1000G dbSNP Medical Literature Clinical Lab Databases OMIM Variant Databases COSMIC HGMD $$$ HGMD $$$ Research Lab Databases Largely absent from the public domain Largely without standardized assertions
  8. 8. Review of Published Pathogenic Variants Found in WGS 3-5 million variants3-5 million variants ~20,000 Coding/Splice Variants~20,000 Coding/Splice Variants 20-40 “Pathogenic” Variants 20-40 “Pathogenic” Variants Published as Disease-Causing Genes <1% Rare CDS/Splice VariantsRare CDS/Splice Variants LOF in Disease Associated Genes 10-20 Variants10-20 Variants Review evidence for gene-disease association and LOF role Review evidence for variant pathogenicity 92% Excluded 67% Excluded Acknowledgements: Heather McLaughlin Kalotina Machini Ozge Ceyhan Birsoy Matt Lebo Danielle Metterville Weak disease association 65% Not medically relevant 33% Somatic 2% MedSeq Project: PI: Robert Green
  9. 9. Rating System for Gene Dosage Highest -- 3, 2, 1, 0, unlikely dosage sensitive -- Lowest
  10. 10. Proposed Revisions to ACMG Guideline for Interpretation of Sequence Variants ACMG Sue Richards, Chair Heidi Rehm, Co-chair Sherri Bale Wayne Grody David Bick Madhuri Hegde Soma Das Elaine Spector AMP Elaine Lyon Julie Gastier-Foster CAP Karl Voelkerding Nazneen Aziz On behalf of the ACMG Laboratory Quality Assurance Committee
  11. 11. Terminology Mendelian disease variant terminology • Pathogenic • Likely pathogenic ← (≥90% confidence) • Uncertain significance (VUS) • Likely benign • Benign Replace terms “mutation” and “polymorphism” with “variant” Defined other areas that need variant terminology: Complex traits, Pharmacogenetics, Cancer
  12. 12. Population Data Computational And Predictive Data Segregation Data Other Database Prevalence in affecteds statistically increased over controls PS4 MAF frequency is too high for disorder BSI OR observation in controls inconsistent with disease penetrance BS2 Truncating variant in a gene where LOF is a known mechanism of disease PVS1 De novo (paternity & maternity confirmed) PS2 Well-established functional studies show a deleterious effect PS3 Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before PM5 Multiple lines of computational evidence support a deleterious effect on the gene /gene product PP3 De novo (without paternity & maternity confirmed) PM6 Non-segregation with disease BS4 Patient’s phenotype or FH highly specific for gene PP4 For recessive disorders, detected in trans with a pathogenic variant PM3 Found in case with an alternate cause BP5 Missense in gene where only truncating cause disease BP1 Multiple lines of computational evidence suggest no impact on gene /gene product BP4 Well-established functional studies show no deleterious effect BS3 Located in a mutational hot spot and/or known functional domain PM1 In-frame indels in a repetitive region without a known function BP3 Same amino acid change as an established pathogenic variant PS1 In-frame indels in a non-repeat region or stop-loss variants PM4 Observed in trans with a dominant variant BP2 Functional Data Co-segregation with disease in multiple affected family members PP1 De novo Data Allelic Data Absent in 1000G and ESP PM2 Strong Observed in cis with a pathogenic variant BP2 Reputable database = benign BP6 Strong Very StrongModerateSupporting Supporting Reputable database = pathogenic PP5 Missense in gene with low rate of benign missense variants and path. missenses common PP2 Other Data Benign Pathogenic Increased segregation data
  13. 13. The Scoring Rules for Classification Pathogenic 1 Very Strong AND 1 Strong OR ≥2 (Moderate OR Supporting) 2 Strong 1 Strong AND ≥3 Moderate OR ≥2 Moderate and 2 Supporting OR ≥1 Moderate and 4 Supporting Likely Pathogenic 1 Very strong or Strong AND ≥1 Moderate OR ≥2 Supporting ≥3 Moderate ≥2 Moderate AND 2 Supporting ≥1 Moderate AND 4 Supporting Very Strong: PVS1 Strong: PS1-PS4 Moderate: PM1-PM6 Supporting: PP1-PP5 Stand-Alone: BA1 Strong: BS1-BS4 Supporting: BP1-BP6 Benign 1 Stand Alone OR ≥ 2 Strong Likely Benign 1 Strong and ≥1 Supporting OR >2 Supporting Uncertain Significance If other criteria are unmet or arguments for benign and pathogenic are equal in strength
  14. 14. www.ncbi.nlm.nih.gov/clinvar
  15. 15. ClinGenDBClinGenDB Data Flows in ClinGen Expert Curated Variants Case-level Data Variant-level Data ClinVar Data Locus-Specific DatabasesLocus-Specific Databases Clinical LabsClinical Labs ClinicsClinics PatientsPatients Sharing Clinical Reports Project Curation Interface Free-the-Data Campaign Patient Registries ResearchersResearchers Unpublished or Literature Citations InSiGHT CFTR2PharmGKB
  16. 16. Submitter Variants Genes Clinical Labs Harvard Medical School and Partners Healthcare 6996 155 Emory Genetics Laboratory 5252 507 International Standards For Cytogenomic Arrays 4134 17711 University of Chicago 3687 462 Sharing Clinical Reports Project 2045 2 GeneDx 1436 40 ARUP Laboratories 1417 7 LabCorp 1391 140 University Pennsylvania Genetic Diagnostic Lab 68 1 American College of Med Genetics and Genomics 23 1 Ambry Genetics 10 1 26459 General Databases OMIM 24443 3360 GeneReviews 3738 406 28181 LSDB/Researcher – Assertions Submitted Breast Cancer Information Core (BIC) 3793 2 InSiGHT 2360 4 Juha Muilu Group; FIMM, Finland (FIMM) 840 39 ClinSeq Project 425 35 Martin Pollak (Nephrology, BIDMC, Harvard) 234 39 CFTR2 133 1 7785 LSDB/Researcher – No Assertions 111 Submitters 50063 >6957 ClinVar – 117,115 submissions/104,217 unique variants 50,063 variants without assertions from 111 submitters 62,425 variants with assertions from >3360 genes
  17. 17. The Sharing Clinical Reports Project and Free-the-Data Campaign for BRCA1 and BRCA2 Goal: Improve the care and safety of patients through data sharing Method: Request clinical lab reports from clinics and patients Status: >60 clinics and > 200 patients have submitted de-identified reports leading to 4278 variants collected sharingclinicalreports.org Acknowledgements: Bob Nussbaum (UCSF) Danielle Metterville (ICCG) Laura Swaminathan George Riley (NCBI) Larry Brody (BIC) Sharon Terry (Genetic Alliance) Genetic Alliance Staff and SC www.free-the-data.org
  18. 18. ClinVar BRCA1/2 Variants Total 9703 variants – Pathogenic (2232) – Likely pathogenic (26) – Uncertain significance (2191) – Likely benign (565) – Benign (169) – Conflicting interpretations (397) – Literature reference only (4223) Pathogenic Uncertain Significance Likely Benign Benign Not Provided Conflicting Likely Pathogenic
  19. 19. 53 discrepancies: 60% differ based upon likelihood (Benign vs LB, P vs LP) 34% differed VUS vs Likely Pathogenic/Likely Benign 6% differed VUS vs Pathogenic 20% discrepant ClinVar Pilot Project Scope Number of alleles Total submitted to ClinVar 997 Multiple assertions 269 Comparison of three laboratories classifications for variants in 12 RASopathy genes: BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, SHOC2, SOS1, SPRED1
  20. 20. Summary Assertions in ClinVar
  21. 21. Clinical Assertions
  22. 22. ClinVar Evidence Tab
  23. 23. Expert Panel Single-Source Evidence and Methods Provided 1. Assertions without evidence and method provided 2. Literature references without assertions 3. Inconsistency in assertions Multi-Source Consistency Evidence and Methods Provided Practice Guideline ClinVar Review Levels Mendelian Categories: Pathogenic Likely pathogenic Uncertain significance Likely benign Benign (e.g. InSiGHT and CFTR2) (e.g. 23 CF) No stars
  24. 24. ClinVar Expert Panel Designation (3 stars) • Download submission form on ClinVar website • Panel should include multiple institutions and expertise – medical specialists in disease area – medical geneticists – clinical laboratory diagnosticians/ molecular pathologists – researchers relevant to the disease, gene, functional assays and statistical analyses • Process for COI review and updating assertions • Publications or links that describe annotation process • Information provided is reviewed by ClinGen Executive Committee and posted on ClinVar w/designation
  25. 25. Proposal to Develop Level 2 Environment for Submitting and Accessing Case-Level Data
  26. 26. ICCG Annual Conference June 10-12, 2014, Bethesda, MD www.iccg.org clinicalgenome.org
  27. 27. ClinGen Acknowledgements Jonathan Berg Carlos Bustamante Jim Evans David Ledbetter Christa Martin Robert Nussbaum Sharon Plon Heidi Rehm Michael Watson Erica Anderson Swaroop Arahdya Sandy Aronson Euan Ashley Larry Babb Erin Baldwin Sherri Bale Louisa Baroudi Les Biesecker Chris Bizon David Borland Rhonda Brandon Lisa Brooks Michael Brudno Damien Bruno Atul Butte Hailin Chen Mike Cherry Eugene Clark Soma Das Johan den Dunnen Edwin Dodson Karen Eilbeck Marni Falk Andy Faucett Xin Feng Mike Feolo Matthew Ferber Penelope Freire Birgit Funke Monica Giovanni Katrina Goddard Robert Green Marc Greenblatt Robert Greenes Ada Hamosh Bret Heale Madhuri Hegde Ray Hershberger Lucia Hindorff Sibel Kantarci Hutton Kearney Melissa Kelly Muin Khoury Eric Klee Patti Krautscheid Joel Krier Danuta Krotoski Shashi Kulkarni Melissa Landrum Matthew Lebo Charles Lee Jennifer Lee Elaine Lyon Subha Madhavan Donna Maglott Teri Manolio Rong Mao Daniel Masys Peter McGarvey Dominic McMullan Danielle Metterville Laura Milko David Miller Aleksander Milosavljevic Rosario Monge Stephen Montgomery Michael Murray Rakesh Nagarajan Preetha Nandi Teja Nelakuditi Elke Norwig-Eastaugh Brendon O’Fallon Kelly Ormond Daniel Pineda-Alvaraz Erin Ramos Darlene Reithmaier Erin Riggs George Riley Peter Robinson Wendy Rubinstein Shawn Rynearson Cody Sam Avni Santani Neil Sarkar Melissa Savage Jeffery Schloss Charles Schmitt Sheri Schully Alan Scott Chad Shaw Steve Sherry Weronika Sikora-Wohlfield Bethanny Smith Packard Tam Sneddon Sarah South Marsha Speevak Justin Starren Jim Stavropoulos Greer Stephens Christopher Tan Peter Tarczy-Hornoch Erik Thorland Stuart Tinker David Valle Steven Van Vooren Matthew Varugheese Yekaterina Vaydylevich Lisa Vincent Karen Wain Meredith Weaver Kirk Wilhelmsen Patrick Willems Marc Williams Eli Williams

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