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

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

Genomic testing is

(relatively) straightforward

Variant interpretation is not…

5

4

3

2

1

Pathogenic

Likely pathogenic

Uncertain significance

Likely benign

Benign

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????

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

Change in clinical management/treatment options

SNV classification laboratory based EQA

2016 - Does it depend on the individual?

2016 - Does it depend on the individual?

Consistently

inconsistent

2017 & 2018 – Implementation of ACMG guidelines

ISO 15189:2012

Genomics Training Assessment & Competency Tool

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

Variant Assessment Module

List of variants provided

Clinical details available

Enter evidence and

classify variant

Variant Assessment Module

List of variants provided

Clinical details available

Enter evidence and

classify variant

Demonstrate competency

… or any training needs

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

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

SNV Classification Trial 2018

SNV Classification Trial 2018

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!

BRCA1/BRCA2 variant classification EQA run 2

Correct classifications by participants

BRCA1/BRCA2 variant classification EQA run 2

For 8 variants - the correct classification was assigned by >70% participants

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

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

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

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

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

Variant sourcing laboratories and assessors

EQA Scientific advisory groups (SAGs)

GenQA EQA team

Expert Advisors

Acknowledgements

The participants

Contact us on info@genqa.org