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The BRCA Share™ Consortium
a novel public/private partnership
to promote BRCA data sharing
Prof. C. Béroud, AMU, France
Ju...
1. What is BRCA Share™?
BRCA Share™ is a novel gene datashare initiative
➛ scientists (research) open access
➛ commercial ...
BRCA Share was Officially launched on April 21st 2015 and website opened on July 1st 2015
1. What is BRCA Share™?
2. Where do we stand?
BRCA Share™ is well adopted by the community
2. Where do we stand?
BRCA Share™ is well adopted by the community with >1,000 registered users from 428
institutions from...
3. Data from private companies have now been added
BRCA Share™ has incorporated data from the private partners, available ...
3. Data from private companies have now been added
Addition of 505 new BRCA1 mutations (+25.0%)
Addition of 865 new BRCA2 ...
4. BRCA Share™: BRCA1 mutations profile
3.1 %
78.8 %
42.0 %
18.1 %
4.5 %
5.6 %
56.0 %
0.8 %
33.1 %
4. BRCA Share™: BRCA2 mutations profile
0.8 %
83.8 %
52.9 %
15.4 %
3.3 %
5.9 %
64.9 %
0.9 %
25.0 %
4. BRCA Share™: BRCA mutations profile
BRCA1 BRCA2
Large rearrangements 4.4% 0.8%
Small rearrangements 78.8% 83.8%
Missens...
5. Does BRCA Share™ benefit its partners?
Every partner submits its own annotations
Data are curated by the French consort...
5. Does BRCA Share™ benefit its partners?
139
58
142 119
BRCA1 shared variants
458
Partner #3Partner #2
Partner #1
5. Does BRCA Share™ benefit its partners?
BRCA1 shared variants annotated as VUS by at least one partner
109/139
42/58
91/...
5. Does BRCA Share™ benefit its partners?
BRCA1 shared variants annotated as VUS by at least one partner with class
1/2/4/...
342 VUS129
5. Does BRCA Share™ benefit its partners?
Every partner submits its own annotations
Data are curated by the Fre...
5. Does BRCA Share™ benefit its partners?
Every partner submits its own annotations
Data are curated by the French consort...
342 VUS129 ➛ 37.8% of shared BRCA1 VUS
could be reclassified
BRCA1
6. How will VUS’s be reclassified?
BRCA1 VUS Reclassifi...
752 VUS246
➛ 32.7% of shared BRCA2 VUS
could be reclassified
BRCA2
6. How will VUS’s be reclassified?
BRCA2 VUS Reclassifi...
6. How will these VUS be reclassified?
All partners benefit from data sharing
 Reclassification of shared VUS as:
 Patho...
7. VUS Classification
…Other benefits include the immediate advantage of an established data curation
and VUS interpretati...
7. VUS Classification: key role of the French consortium
Evidences are collected and analyzed by members of the network of...
7. VUS Classification: key role of the French consortium
Criteria for classification
• Consensual determination of the fun...
7. BRCA Share™ partners annotations
Classifications from academic and commercial partners are similar (97.8%)…
79.3% same ...
7. BRCA Share™ partners annotations
Compare evidence:
 Access to more recent data?
 Unpublished data?
If no consensus:
...
7. BRCA Share™ VUS classification
To All Our Users Who Continue to Make BRCA Share™
A Success and Encourage Us to Continue
8. BRCA-Share™ partners
Stéphane BEZIAU
Yves-Jean BIGNON
Brigitte BRESSAC-DE PAILLERETS
Alain CALENDER
Chantal DELVINCOURT...
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The BRCA Share(TM) Consortium - Christophe Beroud

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A description of the BRCA Share Consortium

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The BRCA Share(TM) Consortium - Christophe Beroud

  1. 1. The BRCA Share™ Consortium a novel public/private partnership to promote BRCA data sharing Prof. C. Béroud, AMU, France June 2016
  2. 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. 3. BRCA Share was Officially launched on April 21st 2015 and website opened on July 1st 2015 1. What is BRCA Share™?
  4. 4. 2. Where do we stand? BRCA Share™ is well adopted by the community
  5. 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. 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. 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. 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. 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. 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. 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. 12. 5. Does BRCA Share™ benefit its partners? 139 58 142 119 BRCA1 shared variants 458 Partner #3Partner #2 Partner #1
  13. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 25. 7. BRCA Share™ VUS classification
  26. 26. To All Our Users Who Continue to Make BRCA Share™ A Success and Encourage Us to Continue
  27. 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

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