variable variants - the genqa story · 2019-06-26 · ensuring quality end to end dna extraction...
TRANSCRIPT
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Collaboration between CEQAS and UK NEQAS for Molecular Genetics
Member of consortium
Variable Variants - the GenQA story
Dr Sandi Deans Consultant Clinical Scientist
Director, GenQA, Edinburgh, UK
National Scientific & Laboratory Lead for Genomics, NHS England, London, UK
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Ensuring quality end to end
DNA extraction
DNA quality
DNA quantity
Genotyping accuracy
Interpretation Reporting
Sample
collection Consultation
Pre-test referral
Pre-test
consultation/
Referral
Sample Analysis Interpretation Reporting Consultation MDT
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Genomic testing is
(relatively) straightforward
Variant interpretation is not…
5
4
3
2
1
Pathogenic
Likely pathogenic
Uncertain significance
Likely benign
Benign
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SNV classification laboratory based EQA
My local lab classified the
variant as pathogenic and I
can offer PND
I have tested her sister and the lab classed the variant as
a UV????
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Aim to assess the classification of sequence variants
Provided since 2012 – 6 years of data
Not disease based as want to assess the process
Three clinical cases per EQA run and some cases have >1 variants
EQA Case
Kyle Barnes (dob 15/02/1989) is presenting with pulmonary stenosis and has short stature
and a webbed neck. His mother also appears to have features of Noonan syndrome and a
local Consultant Clinical Geneticist has requested testing Kyle for Noonan Syndrome.
Your laboratory has carried out next generation sequencing for a panel of genes within the
RASMAPK pathway - BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NF1, NRAS, PTPN11,
RAF1, SHOC2, SOS1, SPRED1 and RIT1.
The heterozygous variant c.922A>G was detected in the PTPN11 gene (LRG_614t1).
SNV classification laboratory based EQA
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Change in clinical management/treatment options
SNV classification laboratory based EQA
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2016 - Does it depend on the individual?
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2016 - Does it depend on the individual?
Consistently
inconsistent
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2017 & 2018 – Implementation of ACMG guidelines
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ISO 15189:2012
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Genomics Training Assessment & Competency Tool
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Sample Reception
Duty Scientist
Tumour content
assessment
Test data analysis
Sequence variant
interpretation
Report authorisation
Sample Reception
Duty Scientist
Tumour content
assessment
Test data analysis
Sequence variant
interpretation
Report authorisation
Sample Reception
Duty Scientist
Tumour content
assessment
Test data analysis
Sequence variant
interpretation
Report authorisation
GenQA website access
Task scenarios randomly generated
Automated assessment
Complete at your own pace
Training/Performance reviews
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Variant Assessment Module
List of variants provided
Clinical details available
Enter evidence and
classify variant
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Variant Assessment Module
List of variants provided
Clinical details available
Enter evidence and
classify variant
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Demonstrate competency
… or any training needs
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Line managers can view all details entered by individuals
The visual data field can be used to view the scenario
Record outcomes/discussion
Override results based on local practice
Internal laboratory review
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SNV Classification Trial Free to participate June 2018
Access to 5 variants to assess
pathogenicity according to
ACMG-AMP Guidelines
What was involved?
571 participants registered
142 used the scenario
82 participants completed all 5 variants
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SNV Classification Trial 2018
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SNV Classification Trial 2018
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BRCA1/BRCA2 variant classification
in ovarian cancer EQA
Collaboration
Aim to improve patient outcomes: demonstrating competence in
BRCA1/BRCA2 variant classification for PARPi treatment stratification
The top three participant countries were China, Spain and France
Set of 15 variants Randomised to prevent collusion!
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BRCA1/BRCA2 variant classification EQA run 2
Correct classifications by participants
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BRCA1/BRCA2 variant classification EQA run 2
For 8 variants - the correct classification was assigned by >70% participants
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BRCA1/BRCA2 variant classification EQA run 2
Remaining
7 variants <50% of
participants applied
correct
classification Variants were:
• Duplication of exons 13 & 14
• Substitution at the intron/exon acceptor site
• Synonymous and non-synonymous amino
acid changes
• Splicing variant
• Intronic deletion
• Delins
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Panel 0-10
Use of ACMG guidelines1
0
1
2
3
4
5
6
7
8
9
Arg
en
tin
a
Au
stra
lia
Au
stri
a
Bra
zil
Can
ada
Ch
ina
Co
lom
bia
Co
sta
Ric
a
Cyp
rus
Cze
ch R
epu
blic
De
nm
ark
Esto
nia
Fin
lan
d
Fran
ce
Ger
man
y
Gre
ece
Ho
ng
Ko
ng
Ind
ia
Ind
on
esi
a
Ire
lan
d
Ital
y
Mac
ed
on
ia
New
Zea
lan
d
No
rway
Po
lan
d
Ro
man
ia
Ru
ssia
Sin
gap
ore
Slo
ven
ia
Sou
th A
fric
a
Spai
n
Swed
en
Swit
zerl
and
Taiw
an
Thai
lan
d
UK
Uru
guay
Nu
mb
er
of
par
tici
pan
ts
Country
ACMG with evidence ACMG without evidence
27% of overall participants used ACMG guidelines from 37/59 countries
1 Richards et al. Genet Med 2015;17:405–424
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Copy Number Variant Surveys
2015 - 2018
Online survey for participants of prenatal array EQAs
60/80 contacted laboratories participated
Clinical referral indication, sample type, gestational age
CNVs given with co-ordinates + indication of gain or loss
Stated whether de novo or inherited or unknown
Required to categorise the CNV using their local policy
In 2017 & 2018 also included
Consistent with U/S and would you report the CNV?
Provide a postnatal CNV survey
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40%
24%
31%
27%
33%
27%
85% 40%
45%
45%
73%
4%
0
1
2
3
4
5
6
0 1 2 3 4 5 6 7
CN
V C
lass
ific
atio
n
Case Number
Prenatal CNV Detection Survey 2018
Classification
5 Pathogenic
4 Likely Pathogenic
3 VOUS
2 Likely Benign
1 Benign
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BRCA variant EQA with EMQN *FREE TO PARTICIPATE*
Laboratory based
Pathogenicity of
sequence variants EQA
Variant classification trials for individuals
SNVs
CNVs
Haematological variants
*FREE TO PARTICIPATE*
Laboratory based CNV classification Prenatal
Postnatal
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Variant sourcing laboratories and assessors
EQA Scientific advisory groups (SAGs)
GenQA EQA team
Expert Advisors
Acknowledgements
The participants
Contact us on [email protected]