development of rules for the interpretation of mismatch repair gene variants based on the 5-tiered...
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Development of rules for the interpretation of mismatch repair
gene variants based on the 5-tiered IARC classification system
On behalf of the InSiGHT Variant Interpretation Committee
5° Biennial Human Variome Project MeetingParis, 22-05-2014
INTERNATIONAL SOCIETYINTERNATIONAL SOCIETYFOR GASTROINTESTINALFOR GASTROINTESTINALHEREDITARY TUMOURSHEREDITARY TUMOURS
DEPT. MEDICAL GENETICSDEPT. MEDICAL GENETICSCATHOLIC UNIVERSITYCATHOLIC UNIVERSITY
ROMEROME
Human Mutation (2008) 29:1282–1291.
InSiGHT Mutation Database:data cleaning, nomenclature standardization and systematic data review
12,645 MMR gene submissions
10 Source unknown / non-
existant
3,468 nomenclature alterations
(12 not resolvable)
Duplicate entries resolved
230 Somatic7 EPCAM
132 Synthetic
2,360 unique constitutional MMR
gene variants
(MSH2, MLH1, MSH6, PMS2)
Criteria development process
• Used modified Delphi approach– http://en.wikipedia.org/wiki/Delphi_method
• Evolution of criteria – Started with the 117 most commonly cited variants with
discordant interpretation– Iterative amendments & clarifications over 12 meetings
• Quantitative (multifactorial) or qualitative evidence considered
• Work towards fully quantitative (Bayesian), recognising limits– Calibration of in silico algorithms
Current Multifactorial Likelihood Model
Quantitative classification
MMR
Sequence
Variant+ =
Thompson et al Hum Mutat, 2013. 34(1): p.200-09.
Require ≥2 data points to promote robust classification
QUALITATIVE RULES:POINTS OF EVIDENCE
① Co-segregation
② Tumor molecular characteristics: MSI, IHC (BRAF)
③ Population frequency
④ Risk estimated from case-control studies
⑤ Presence of the variant on different haplotypes across LS families
⑥ Type of sequence variation
⑦ Functional protein assays
⑧ mRNA assays
⑨ Co-occurrence of the variant with a clearly pathogenic variant in the same gene and CMMRD phenotype
Qualitative points of evidence
5’…TCT CAA AAA TTT ACG…3’ S Q K F T
5’…TCT CAA TAA TTT ACG…3’ S Q *
Sequence-based
Segregation data Tumour data Frequency data Co-occurrence in trans
In vitro data
Presence/absence of haematological
malignancies, childhood cancers – CMMR-D phenotype
Clinical/molecular Functional
• Major issue in classification process was conflicting data from functional assays
• Functional assay subcommittee formed to tackle the issue
• Flowchart developed to assist assay interpretation
Functional assay interpretation
Class 5 Pathogenic:
Class 4 Likely pathogenic:
Class 3 Uncertain:
Class 2 Likely not pathogenic:
4 points of evidence:
Abrogated function or CMMRD or
different background haplotypes
Co-segregation with disease (~LR
10:1)≥2 tumors with LS
molecular phenotype
Absence in 1000 genomes
PP >0.99
or
Nonsense/frameshift
Full inactivation of variant allele by
splicing aberration
Large deletion
Large duplication confirmed to
encode a frameshift leading to NMD
or
or
or
or
2 points of evidence:
PP 0.95-0.99
Canonical splice site, untested for
splicing
Co-segregation with disease
(~LR 5:1)
Or
≥2 tumors with LS molecular phenotype
Abrogated function or CMMRD or
different background haplotypes
or
or
Synonymous or intronic variant with no mRNA
aberration
AF ≥1% in specific ethnic group
2 points of evidence if proficient function,
otherwise 3 points of evidence required:
Proficient function or co-occurrence with no CMMRD
AF 0.01-1%
No co-segregation with disease (~LR 0.01:1)
≥3 MSS CRC or inconsistent IHC
tumors
Odds Ratio with upper 95% CI <5 in
case-control studies
PP 0.001-0.049
or
or
or
Class 1 Not pathogenic:
3 points of evidence if proficient function,
otherwise 4 points of evidence required:
AF ≥1% in control reference groups
Proficient function or co-occurrence with no CMMRD
AF 0.01-1%
No co-segregation with disease
(~LR 0.01:1)
≥3 MSS CRC or inconsistent IHC
tumors
Odds Ratio with upper 95% CI <4 in
case-control studies
PP <0.001
or
or
Insufficient evidence to
classify
PP 0.05-0.949
or
Nature Genetics 46, 107–115 (2014)
Rationale underlying Class 5 criteria
Class 5: evidence from tumor molecular pathology
Criterion
• > 2 tumors with MSI-H and/or appropriate IHC loss
Rationale
• Provides evidence that the variant is associated with the clinical phenotype. Assumed conservative LR > 5:1 for tumor data
Transparent presentation of summary data for classifications
www.insight-group.org/classifications
Future Perspectives
• Rule revision (ie, de novo mutations)
• Revise classifications
• Gene-specific rules
• Intermediate penetrance variants
• Further genes (APC, MUTYH,…)
InSiGHT Variant Interpretation Committee (VIC)
Bryony A. Thompson
Amanda B. Spurdle
Marc Greenblatt
John-Paul Plazzer
Kiwamu Akagi
Fahd Al-Mulla
Bharati Bapat
Inge Bernstein
Gabriel Capella
Johan T den Dunnen
Desiree du Sart
Mark Farrell
Susan Farrington
Ian Frayling
Established Yokohama, 2007
Ming Qi
Rajkumar Ramesar
Brigitte Royer-Pokora
Rodney Scott
Rolf Sijmons
Carli Tops
Thomas Weber
Juul Wijnen
Michael Woods
Lene Rasmussen
David Goldgar
Sean Tavtigian
Finlay Macrae
Maurizio Genuardi
Thierry Frebourg
Chris Heinen
Elke Holinski-Feder
Maija Kohonen-Corish
Suet Yi Leung
Annika Lindblom
Kristina Lagerstedt
Alexandra Martins
Pal Moller
Monika Morak
Minna Nystrom
Aurelie Fabre
Paivi Peltomaki
Marta Pineda
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