acgs: standardisation of variant interpretation and reports · acgs guidelines published october...
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ACGS: Standardisation of variant interpretation and reports
Sian Ellard
South West NHS Genomic Medicine Centre
Festival of Genomics, 31st January 2018
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Genome sequencing for clinical diagnosis
2018
Genome sequencing
as an NHS test
October 1st 2018
2015
100,000 Genomes Project
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Whole genome sequencing is (relatively) straightforward
Variant interpretation is not…
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Genetic variants
The human genome consists of 3 billion DNA bases that encode ~20,000 genes
Each genome differs by 3-4 million variants
Each individual has ~150 rare variants that are predicted to affect
protein function (Lek et al Nature 2016 ExAC MAF<0.1%)
There are many different types of variants e.g. missense, splicing,
nonsense, small deletions, insertions, gene copy number changes and chromosome rearrangements
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Innovation
Standardisation
Quality improvement
The 100,000 Genomes Project is catalysing laboratory service transformation at pace and scale.
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5
4
3
2
1
Pathogenic
Likely pathogenic (>90%)
Uncertain significance
Likely benign (<90%)
Benign
New variant interpretation guidelines from USA 2015
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Summary of evidence framework
Richards et al 2015 Genetics in Medicine; Jarvik and Browning 2016 Am J Hum Genet
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Rules for combining criteria to classify variants
5
4
3
2
1
Pathogenic
Likely pathogenic (>90%)
Uncertain significance
Likely benign (<90%)
Benign
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Variant classification evidence
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Assess the evidence for a variant across all patients for which information is available
Publications
Public/NHS databases
Laboratory database
Patient referred for testing
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Assessing variant pathogenicity
Search databases: HGMD Pro DECIPHER ClinVar Gene specific Google scholar
Protein analysis: In vitro modelling Functional studies Animal models
Clinical data: Muscle biopsy Nerve conduction studies Drug response Metabolic profile Biochemistry Immunology
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Fetus 1 TOP 22/40
Rapidly progressing ventriculomegaly No DNA
Fetus 2 TOP 18/40
Rapidly progressing ventriculomegaly No genetic diagnosis
2
Case example – lethal fetal disorder
POMGNT1 p.Arg497Gln/N POMGNT1 p.Arg497Gln/N
POMGNT1 p.Arg497Gln/p.Arg497Gln
Exome sequencing (23,244 genes) of parental DNA samples
Not homozygous
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Evidence: PM1, PM2, PP3, PP1 (1/7 need 1/8)
One report of this variant on ClinVar database An e-mail to the Emory lab provides a key piece of
evidence; the variant is homozygous in a patient with the characteristic phenotype
MDT discussion (referring clinical geneticist and lab scientists with input from external experts) concludes that variant is “likely pathogenic”
Case example – lethal fetal disorder
Evidence: PM1, PM2, PP3, PS4_Supporting, PP4, PP1 (1/7 need 1/8)
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Putting the ACMG guidelines into practice
Principles
Use the guidelines as a framework to determine whether there is sufficient evidence to classify the variant as likely pathogenic or likely benign
Incorporate clinical data (functional and gene specific phenotype)
Use your professional judgement
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Variant classification and interpretation workshop 4th November 2016
Introduction to ACMG guidelines
Early adopters’ experience
Aligning CNV classification
Integrating clinical phenotype and interpretation
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Improving the quality of variant interpretation for clinical diagnosis
Train the trainers: February 28th 2017
24 Regional centres represented
Emma Baple
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Monthly WebEx for regional trainers
Cases
Two cases per month circulated
Submit classifications before meeting
Review cases at meeting
Produce worked case examples
On-line resource (Jostle)
Share ideas for local implementation
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Disease-specific subgroups
Cancer
Cardiac
Familial hypercholesterolaemia
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ACGS guidelines published October 2017
PS3 – (Strong) Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or
gene product.
Functional studies can include in vitro functional assays (eg. reporter gene assays for transcription factors),
measurement of proteins in vivo (eg. biochemical tests on patient samples) mRNA analysis for suspected splicing
variants and other investigations where the results are pathognomonic of a specific single genetic cause of a disorder.
See Table 2 for a list of examples.
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Functional domain or mutation hot spot?
PM1 – (Moderate) Located in a mutational hot spot and/or critical and well-established
functional domain (e.g., active site of an enzyme) without benign variation.
Plot functional domains, ExAC variants, HGMDPro/ClinVar/LOVD etc variants and
Consurf/conservation plots to show reported pathogenic variants, proxy population and
benign variants and amino acid conservation for a region of a gene.
PM1 Plot for SOX10 p.(Ala132Val)
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NOTCH2 p.Arg1895His variant in patient with ?Alagille syndrome
http://cardiodb.org/allelefrequencyapp/
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The ACMG guidelines are evolving…
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Aim
To develop an improved, standardised report template for
clinical genomic tests performed in UK laboratories. The
standardised report template will communicate the results of
clinical genomic tests in a format that facilitates
understanding of the results by a specialist or non-specialist
healthcare professional and the patient or their family.
Developing a standardised report template
Working group: Steve Abbs, Ed Blair, Diana Eccles, Sandi Deans, Sian Ellard
(Chair), Helen Firth, David Gokale, Lucy Jenkins, Tracy Lester, Dom
McMullan, Sian Morgan, Bill Newman, Chris Patch and Richard Scott
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F-shaped reading pattern
20-30% text actually read
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Standard report template
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Standard report template
Appendix
Variant classification and MDT meeting summary form
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Standard report template
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Thank you
ClinGen team (USA) All the UK regional trainers Reporting template working group members