progress of the insight mismatch repair gene database and variant interpretation committee -...

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gene database and variant interpretation committee – application of classification rules and dissemination of results. Finlay Macrae Secretary, International Society for Gastrointestinal Hereditary Tumours For the InSiGHT Variant Interpretation Committee Head, Colorectal Medicine and Genetics, The Royal Melbourne Hospital Professor of Medicine, Depts of Medicine, Melbourne and Monash Universities, Victoria, Australia HVP meeting, May 2014 UNESCO Building, Paris

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Locus-specific databases (LSDBs) which accept submissions of variants and their interpretation from diagnostic and research laboratories are subject to problems of duplicate entries, limited annotation of relevant clinical and experimental data, and variable quality of in silico analyses. In addition, ad hoc or generic criteria for interpretation lack refinement for gene specific interpretation, and do not draw on the specific expertise of clinicians and scientists directly working in the field relevant to the genes in question. As a result, interpretation of the same variant submitted from different sources can be discordant, leaving the database and the clinical field open to uncertainty, detracting from its utility for clinical application. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) has fostered the integration of all major mismatch repair databases into a single LSDB. InSiGHT has developed a coordinated approach to the authoritative interpretation of mismatch repair gene variants, engaging a range of gene specific experts, and drawing on comprehensive clinical and experimental information sourced from the published literature and from its own members. The InSiGHT Variant Interpretation Committee comprised of 40 experts in the mismatch repair field was tasked with variant review and classification on a pro bono basis. InSiGHT developed governance and support through incorporation, to protect the committee from possible legal challenge related to clinical use of its conclusions. The Committee applied a standardized classification scheme to constitutional variants in the Lynch Syndrome genes MLH1, MSH2, MSH6 and PMS2, reviewing all clinical and functional data available for the variants [3]. All 2,360 unique sequence alterations were considered and classified. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinically important misclassifications were identified for unique variants initially submitted as not pathogenic (54 unique variants reclassified as pathogenic and 25 reclassified as likely pathogenic) and unique variants submitted as pathogenic (28 unique variants reclassified as not pathogenic, 16 reclassified as likely not pathogenic and 218 reclassified as uncertain clinical significance). Importantly, the consensus results have been disseminated online through the InSiGHT database and ClinVar. Consistent clinical management based on transparent evaluation is now possible for the 1,370 variants that are not obviously protein truncating (e.g. missense, single amino acid indels) based on their nomenclature. This large-scale endeavour demonstrates the value of multidisciplinary collaboration for curation and classification of variants in public locus-specific databases.

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Page 1: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

Progressive of the InSiGHT mismatch repair gene

database and variant interpretation committee –

application of classification rules and dissemination

of results.

Finlay MacraeSecretary, International Society for Gastrointestinal Hereditary Tumours For the InSiGHT Variant Interpretation CommitteeHead, Colorectal Medicine and Genetics, The Royal Melbourne HospitalProfessor of Medicine, Depts of Medicine, Melbourne and Monash Universities, Victoria, AustraliaHVP meeting, May 2014UNESCO Building, Paris

Page 2: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae
Page 3: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

What is InSiGHT• The International Society for

Gastrointestinal Hereditary Tumours formed with the merger of the Leeds Castle Polyposis Group and ICG HNPCC in 2005

• Incorporated in 2009 • Maintains a database of MisMatch Repair

and other genes responsible for GI cancer DNA variants through its website

www.insight-group.org

Page 4: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

InSiGHT and theHuman Variome Project

ConsensusInSiGHT meeting Yokohama,

March 2007

Page 5: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

InSiGHT Database:A lead LSDB for the

HVP• Curator: JohnPaul Plazzer (Colorectal Medicine

and Genetics, RMH, and Human Variome Project)

Page 6: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

MMR mutation Identified

(DNA Lab)

IHC &/or MSI data added

(Histopathology)

Interpretation of genotype

(Clinicians & Lab)

Virtual pathology added

(Histopathology)

Functional data added

(Research Labs)

Clinical phenotype added

(Clinicians)

Identified dataset stored locally

(Family Cancer Clinic)

De-identified data stored with InSiGHTVariant Interpretation Committee

(InSiGHT)

DbGaP (NCBI)ClinVarUCSC

Data from other centres can be

submitted to update information

Page 7: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

InSiGHT/HVP databaseAchievements

• Merge of MMR (Mike Woods), functional assay (R Sijmons) with InSiGHT databases – 2008

• Full time InSiGHT curator appointed - 2010 in Melb JohnPaul Plazzer

• Data submission..data submission…, Germany, Sweden, Denmark, Australia, US CFR, China, UK, Quest Diags

• InSiGHT Variant Interpretation Committee : Gene specific criteria for pathogenicity – 2011

• Nature Genetics Publication on Variant Interpretation accepted(B Thompson et al) – 2013

• Strongly endorsing Nature Genetics Editorial

• Microattribution: Nature Genetics accepted (Thompson B et al)

• “Follow a Variant”

• MMR Functional assay calibration grant: US RO1 grant(S Tavtigian,M Greenblatt) • -2013• International Mismatch Repair Consortium: NHMRC funded 2013• Clin Var: NCBI engaged 2013 US

Page 8: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae
Page 9: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

The InSiGHT Database• As of the end of December 2012 there were 12,635

submissions to the InSiGHT database of 2,730 unique MMR gene variants lodged in the InSiGHT database.

• Now (April 2014) there are 14,304 submissions of 2,888 unique variants

• Briefly, multiple lines of evidence were required for classification, and evidence for each variant had to include data associating the variant with both clinical and functional consequences (Online Methods).

Page 10: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

InSiGHT Database Visitor count

Database ‘hits’ in 2012 per month

Can infer from these numbers that visitors use the InSiGHT database multiple times per month

Page 11: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

Should I request colonoscopy?

Donna-Marie Ian25 24

Positive FHMSI high tumourMLH1 leu559arg

Missense Not inherited

Robert HofstraRolf SijmonsWestern:no expressionPulldown: no interaction

MAPP-MMR and SIFT v2Suggest pathogenic

Polyphen inconclusive

Reported Belvederesi EJHG2006

Page 12: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

August 2010 China National Highway 110 traffic jam, China, world’s worst traffic jam ever….more than 100 kilometres from August 14 - 26, inc. at least 11 days of total gridlock.

Page 13: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

InSiGHT Variant Interpretation

Committee

Modus operandi• Chair appointed by Council: Maurizio Genuardi (Italy)• Invitations for core and extended committee memberships• Qualitative approach to classification discussed, circulated, and agreed • Initial set of missense variants with 3 lines of evidence classified

according to approach agreed across the committee• Variant list for discussion is circulated to extended committee – any

additional available data canvassed• All data is then assembled by curator for Core Committee plus rolling

other membership to classify at international teleconferences (sponsored)

• One line entry to be included on InSiGHT database describing outcomes• Later, preliminary approach to all InSiGHT members to seek all available

information of variants under consideration at each meeting• InSIGHT members encouraged to submit data at each contact, and

signal variants of particular clinical concern for Committee consensus

Page 14: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

InSiGHT Variant Interpretation

Committee • M Genuardi (Italy, Chair)

• JP Plazzer (Curator)• F Macrae (Sec, InSiGHT)• A Spurdle (Australia)• B Thomson (Australia)• M Woods (Canada)• R Sijmons (Netherlands)• P Peltomaaki (Finland)• M Greenblatt (USA)• I Frayling (UK)• J Burn (UK)• M Dunlop (UK)• S Farrington (UK)• B Royer Pokora (Germany)• E Holinski Feder (Germany)• G Moeslein (Germany)• I Blanco (Spain)• G Capella (Spain)• D Du Sart (Australia)• M Kohonen Corish (Australia)• R Scott (Australia)• B Talseth (Australia)

• R Ramesar (South Africa)• M Qi (China)• R Hofstra (Netherlands)• M Vihinen (Finland)• M Nystrom (Finland)• T Weber (USA)• S Tavtigian (USA)• D Golgar (USA)• C Heinen (USA)• S Lipkin (USA)• A Lindblom (Sweden)• K Akagi (Japan)• F Al-Mulla (Kuwait)• I Bernstein (Denmark)• F Wikman (Denmark)• T Frebourg (France)• S. Olschwang (France)• S Leung (Hong Kong)• T Liu (Sweden)• P Moller (Norway)• B Bapat (Canada)• L Rasmussen (Denmark)

Page 15: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

Simplified guidelines describing the levels and types of evidence required for each tier of the classification

Thompson, B. A., Spurdle, A. B., Plazzer, J. P., Greenblatt, M. S., Akagi, K., Al-Mulla, F., ... & Genuardi, M. (2013). Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nature genetics.

Page 16: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

Microsatellite Instability analysis -

Electropherograms

Electropherograms of the fluoresceinated amplification products for the loci BAT26 and BAT25 from colorectal cancer tissue.

Hoang et. al. 1997; Zhou et. al. 1998

Page 17: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

Immunohistochemical detection of Loss of Expression

MLH1

MSH2

MSH6

PMS2

Page 18: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

Altered Classifications• Proportion of five-tiered classifications for all documented constitutional variants in

the database against the original LOVD database classifications assigned by submitters

• Class 5b includes variants that are not obviously truncating but are considered to be pathogenic on the basis of combined evidence

Thompson, B. A., Spurdle, A. B., Plazzer, J. P., Greenblatt, M. S., Akagi, K., Al-Mulla, F., ... & Genuardi, M. (2013). Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nature genetics.

Page 19: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

Final Classifications• Class 5b includes variants that are not obviously truncating but are

considered to be pathogenic on the basis of combined evidence• In addition to the 990 assumed pathogenic truncating or large-deletion

variants (class 5a), consistent medical management is now also possible for the remaining 1,370 not obviously truncating variants; these include 167 class 5 (pathogenic) variants (class 5b) (12%), 183 class 4 (likely pathogenic) variants (14%), 86 class 2 (likely not pathogenic) variants (6%) and 169 class 1 (not pathogenic) variants (12%)

Thompson, B. A., Spurdle, A. B., Plazzer, J. P., Greenblatt, M. S., Akagi, K., Al-Mulla, F., ... & Genuardi, M. (2013). Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nature genetics.

Page 20: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

• Presentation of evidence used for InSiGHT Classification

• http://www.insight-group.org/variants/classifications/

Page 21: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

www.insight-group.org/variants/classifications/

Follow a variant

Page 22: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

Summary• Genetic Medicine is moving centre stage• Genetic testing will move into the routine domain• Failure to apply genetic knowledge kills people• Ability to intervene will drive diagnostics• We must focus on variant analysis

Page 23: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

InSiGHT Variant Interpretation

Committee • M Genuardi (Italy, Chair)

• JP Plazzer (Curator)• F Macrae (Sec, InSiGHT)• A Spurdle (Australia)• B Thomson (Australia)• M Woods (Canada)• R Sijmons (Netherlands)• P Peltomaaki (Finland)• M Greenblatt (USA)• I Frayling (UK)• J Burn (UK)• M Dunlop (UK)• S Farrington (UK)• B Royer Pokora (Germany)• E Holinski Feder (Germany)• G Moeslein (Germany)• I Blanco (Spain)• G Capella (Spain)• D Du Sart (Australia)• M Kohonen Corish (Australia)• R Scott (Australia)• B Talseth (Australia)

• R Ramesar (South Africa)• M Qi (China)• R Hofstra (Netherlands)• M Vihinen (Finland)• M Nystrom (Finland)• T Weber (USA)• S Tavtigian (USA)• D Golgar (USA)• C Heinen (USA)• S Lipkin (USA)• A Lindblom (Sweden)• K Akagi (Japan)• F Al-Mulla (Kuwait)• I Bernstein (Denmark)• F Wikman (Denmark)• T Frebourg (France)• S. Olschwang (France)• S Leung (Hong Kong)• T Liu (Sweden)• P Moller (Norway)• B Bapat (Canada)• L Rasmussen (Denmark)

Page 24: Progress of the InSiGHT Mismatch Repair Gene Database and Variant Interpretation Committee - Application of Classification Rules and Dissemination of Results - Finlay Macrae

International Society for Gastrointestinal Hereditary Tumors

2015June 18-20th

Prof. Benedito Mauro RossiChairman

6th. InSiGHT Meeting - 2015 - Sao Paulo