The BRCA ShareTM Consortium is a public-private partnership that promotes sharing of BRCA genetic data. It has over 35,000 BRCA test results from US and French clinical labs. The goal is to accelerate BRCA research. It is a open user group co-founded by Inserm and Quest Diagnostics. BRCA ShareTM is well adopted internationally. In June 2016, it incorporated new data from private partners, increasing the number of known BRCA mutations. The consortium of French experts helps curate and reclassify variants of unknown significance based on multiple lines of evidence. This benefits all partners through improved annotation of shared variants.

1. The BRCA Share™ Consortium
a novel public/private partnership
to promote BRCA data sharing
Prof. C. Béroud, AMU, France
June 2016

2. 1. What is BRCA Share™?
BRCA Share™ is a novel gene datashare initiative
➛ scientists (research) open access
➛ commercial laboratory organizations (diagnostics) licensed access
to BRCA1 and BRCA2 genetic data
The program’s goal is to accelerate research on BRCA gene mutations
BRCA Share™ is an open user group co-founded by Inserm and Quest Diagnostics
With the support of Inserm Transfert
The BRCA Share™ database now contains variant data for over 35,000 BRCA1/2
gene sequence tests from the largest clinical labs in US and France
Other participants include:

3. BRCA Share was Officially launched on April 21st 2015 and website opened on July 1st 2015
1. What is BRCA Share™?

4. 2. Where do we stand?
BRCA Share™ is well adopted by the community

5. 2. Where do we stand?
BRCA Share™ is well adopted by the community with >1,000 registered users from 428
institutions from 49 countries

6. 3. Data from private companies have now been added
BRCA Share™ has incorporated data from the private partners, available since June 2016
Officially announced June 1st 2016

7. 3. Data from private companies have now been added
Addition of 505 new BRCA1 mutations (+25.0%)
Addition of 865 new BRCA2 mutations (+30.7%)
BRCA1 BRCA2
Pathogenic 21.6% 16.7%
Likely pathogenic 6.7% 5.3%
Neutral 6.9% 5.5%
Likely neutral 15.0% 13.9%
VUS * 49.8% 58.6%
* Note that per-variant VUS rate is not the same as per-patient VUS rate. The
latter is much lower, because most VUS are rare.

8. 4. BRCA Share™: BRCA1 mutations profile
3.1 %
78.8 %
42.0 %
18.1 %
4.5 %
5.6 %
56.0 %
0.8 %
33.1 %

9. 4. BRCA Share™: BRCA2 mutations profile
0.8 %
83.8 %
52.9 %
15.4 %
3.3 %
5.9 %
64.9 %
0.9 %
25.0 %

10. 4. BRCA Share™: BRCA mutations profile
BRCA1 BRCA2
Large rearrangements 4.4% 0.8%
Small rearrangements 78.8% 83.8%
Missense 42.0% 52.9%
Mid-intronic 18.1% 15.4%
Neutral 4.5% 3.3%
Likely neutral 5.6% 5.9%
Likely pathogenic 0.8% 0.9%
Pathogenic 33.1% 25.0%
VUS 56.0% 64.9%

11. 5. Does BRCA Share™ benefit its partners?
Every partner submits its own annotations
Data are curated by the French consortium of experts
Evaluation of BRCA Share benefits:
 A partner submitted a VUS
 This variant was annotated by other partners with enough evidence

12. 5. Does BRCA Share™ benefit its partners?
139
58
142 119
BRCA1 shared variants
458
Partner #3Partner #2
Partner #1

13. 5. Does BRCA Share™ benefit its partners?
BRCA1 shared variants annotated as VUS by at least one partner
109/139
42/58
91/142 100/119
342/458
Partner #3Partner #2
Partner #1

14. 5. Does BRCA Share™ benefit its partners?
BRCA1 shared variants annotated as VUS by at least one partner with class
1/2/4/5 annotation by others
58/109
20/42
23/91 28/100
129/342
Partner #3Partner #2
Partner #1

15. 342 VUS129
5. Does BRCA Share™ benefit its partners?
Every partner submits its own annotations
Data are curated by the French consortium of experts
Evaluation of BRCA Share benefits:
 A partner submitted a VUS
 This variant was annotated by other partners with enough evidence
BRCA1
➛ 37.8% of shared BRCA1 VUS
could be reclassified

16. 5. Does BRCA Share™ benefit its partners?
Every partner submits its own annotations
Data are curated by the French consortium of experts
Evaluation of BRCA Share benefits:
 A partner submitted a VUS
 This variant was annotated by other partners with enough evidence
752 VUS246 ➛ 32.7% of shared BRCA2 VUS
could be reclassified
BRCA2

17. 342 VUS129 ➛ 37.8% of shared BRCA1 VUS
could be reclassified
BRCA1
6. How will VUS’s be reclassified?
BRCA1 VUS Reclassification
➛ Pathogenic 3 (2.3%)
➛ Likely pathogenic 7 (5.4%)
➛ Likely neutral 89 (69.0%)
➛ Neutral 30 (23.3%)

18. 752 VUS246
➛ 32.7% of shared BRCA2 VUS
could be reclassified
BRCA2
6. How will VUS’s be reclassified?
BRCA2 VUS Reclassification
➛ Pathogenic 4 (1.6%)
➛ Likely pathogenic 9 (3.7%)
➛ Likely neutral 193 (78.4%)
➛ Neutral 40 (16.3%)

19. 6. How will these VUS be reclassified?
All partners benefit from data sharing
 Reclassification of shared VUS as:
 Pathogenic mutations ≃ 2%
 Probably pathogenic mutations ≃ 5%
 Likely Neutral mutations ≃ 70%
 Neutral mutations ≃ 23%

20. 7. VUS Classification
…Other benefits include the immediate advantage of an established data curation
and VUS interpretation system and investment by commercial entities in functional
studies to determine VUS pathogenicity

21. 7. VUS Classification: key role of the French consortium
Evidences are collected and analyzed by members of the network of molecular laboratories
Institut Curie (PARIS) Dominique Stoppa-Lyonnet,
Institut Gustave Roussy (VILLEJUIF) Brigitte Bressac-de Paillerets
Centre Oscar Lambret (LILLE) Françoise Révillion
Hospices Civils de Lyon/Centre Léon Bérard (LYON) Alain Calender
Institut Bergonié (BORDEAUX) Nicolas Sevenet, Michel Longy
Institut Claudius Regaud - IUCTOncopole (TOULOUSE) Christine Toulas
Institut Paoli-Calmettes (MARSEILLE) Hagay Sobol
C.H.R.U. Nancy Brabois (VANDOEUVRE-LES-NANCY) Philippe Jonveaux
CHU et Institut Jean Godinot (REIMS) Tan Dat Nguyen
Centre François Baclesse (CAEN) Dominique Vaur
C.H.U. Institut de Biologie - Hôtel Dieu (NANTES) Stéphane Bezieau
Centre Paul Strauss (STRASBOURG) Danièle Muller
Institut Curie Hôpital René Huguenin (St CLOUD) Rosette Lidereau
Centre Georges François Leclerc (DIJON) Sarab Lizard
Centre Jean Perrin (CLERMONT-FERRAND) Y.J. Bignon
CHU Arnaud de Villeneuve (Montpellier) Thierry Maudelonde
Groupe Hospitalier Pitié-Salpêtrière (PARIS) Florent Soubrier

22. 7. VUS Classification: key role of the French consortium
Criteria for classification
• Consensual determination of the functional domains
• Result scores and predictive bioinformatics tools with phylogenetic
conservation: Grantham score, A-GVGD, UMD-Predictor and others ...
• Published causality and/or neutrality scores
• Co-occurrence with one or more deleterious mutations
• Splicing data by RNA studies (splicing assay group)
• Results of functional tests
• Bibliographic data and other databases
• Co-segregation analysis (COVAR group): Common and national approach
for co-segregation analysis in France (all families with the same protocol)

23. 7. BRCA Share™ partners annotations
Classifications from academic and commercial partners are similar (97.8%)…
79.3% same annotation (class 1, 2, 3, 4 or 5)
18.5% same tendency but 1 class difference (class 1/2, 2/3, 3/4 or 4/5)
gene nomenclature cases #1 #2 Curators
BRCA1 c.3608G>A p.Arg1203Gln 9 2 3 1
BRCA1 c.3739G>A p.Val1247Ile 9 1 3 1
BRCA1 c.425C>A p.Pro142His 9 1 3 1
BRCA1 c.5411T>A p.Val1804Asp 18 3 1 1
BRCA2 c.10045A>G p.Thr3349Ala 24 2 3 1
BRCA2 c.8917C>T p.Arg2973Cys 8 1 3 2
BRCA2 c.9699_9702del p.Cys3233TrpfsX15 7 5 3 5
BRCA2 c.316+13A>G 14 1 3 3
… but not always identical
2.2% have discrepancies (≥2 classes)

24. 7. BRCA Share™ partners annotations
Compare evidence:
 Access to more recent data?
 Unpublished data?
If no consensus:
 What evidence is needed for classification?
 Are functional studies an added value?
HDR activity (Lu et al. Nature Communications, 2015)
CRISPR-Cas9
BRCA Share™ will fund studies
BRCA2 functional data (Guidugli et al. Hum. Mutat, 2014)
Minigene reporter assay (Gaildrat et al.
JMG, 2016)

25. 7. BRCA Share™ VUS classification

26. To All Our Users Who Continue to Make BRCA Share™
A Success and Encourage Us to Continue

27. 8. BRCA-Share™ partners
Stéphane BEZIAU
Yves-Jean BIGNON
Brigitte BRESSAC-DE PAILLERETS
Alain CALENDER
Chantal DELVINCOURT
Philippe JONVEAUX
Sarab LIZARD
Michel LONGY
Thierry MAUDELONDE
Danièle MULLER
Tan Dat NGUYEN
Jean-Philippe PEYRAT
Françoise REVILLION
Dominique VAUR
Nicolas SEVENET
Hagay SOBOL
Florent SOUBRIER
Christine TOULAS
Dominique VAUR
David SALGADO
Ghadi RAI
Jean-Pierre DESVIGNES
Gwenaëlle COLLOD-BEROUD
Claude HOUDAYER
Sandrine CAPUTO
Etienne ROULEAU
Nicolas DERIVE
Dominique STOPPA-LYONNET
Corey D BRAASTAD
Crystal M BUELL
Christina DIVINCENZO
Christopher D ELZINGA
Camille R NERY
Izabela KARBASSI
Charles M STROM
Inserm Transfert Team
Stanley LETOVSKY
Edwin TRAUTMAN
Marcia EISENBERG
& Variant Science Team