The Human Variome Project’s ideal world includes a global system for the automated sharing and discovery of our collective genomic knowledge. The Global Collection Architecture is an idealised view of what this might look like.

HVP Country Nodes are responsible for collecting clinically validated genetic variation data from diagnostic laboratories in each country or region of the world. HVP Country Nodes are operated and managed locally, in a manner that respects local ethical, legal and social responsibilities. HVP Country Nodes provide a focal point for HVP related activities in each country, usually in conjunction with the local human genetics societies.

International Gene/Disease Specific Databases collect data from around the world on a single gene or disease, including from all HVP Country Nodes. They provide an expert review function, putting the world’s data in front of international experts who use formal review procedures to make a consensus determination on the functional effect of individual variants.

Introduction
The haemoglobinopathies, collectively, are cause for significant morbidity and mortality, especially in parts of the world where health systems are weak. Children are the most severely affected.

Despite much of the genetics and biology of haemoglobinopathies being known and used successfully in some countries to systematically reduce the burden of disease, many low and middle income countries remain practically untouched by this knowledge and innovation.

There is a risk in countries where the burden of haemoglobinopathies is highest of being left behind in a form of “genomic divide”. Capacity to generate and store quality data on variants, so that it can be shared internationally needs to be established in these countries. This will enable;
• Building the genetic evidence base for better management and delivery of local treatment and care, eventually leading to a cure, and
• Forming a foundation for more broadly-focused genomic medicine by working with national, regional and local health care professionals to raise public awareness of the genetic basis of haemoglobinopathies.

The need
WHO estimates that over 330 000 affected infants are born annually and that haemoglobin disorders account for about 3.4% of deaths in children under 5 years of age. However in some parts of the world, such as West Africa, the death rate of children under 5 years is 18.4%. Globally, an estimated 7% of pregnant women carry one of the known forms of inherited haemoglobin disorders, and over 1% of couples are at risk. These figures underestimate the overall disease burden, because these disorders affect families, not just individuals.

The prevalence of haemoglobinopathies is expected to increase in coming years as a result of unmanaged conditions in most parts of the world. Additionally, increased migration of people will lead to greater spread, exposing health systems in many more countries to the demands for genomic medicine.

Participating countries

1. Malaysia
2. Cyprus
3. France
4. Italy
5. Singapore
6. United Kingdom (UK)
7. Australia
8. Bangladesh
9. Belgium
10. China
11. India
12. Indonesia
13. Iran
14. Netherland
15. Nigeria
16. Pakistan
17. Portugal
18. South Africa
19. Spain
20. Thailand
21. Turkey
22. Vietnam
23. Brazil
24. Cambodia
25. Egypt
26. Nepal
27. Philippines
28. Rep. of the Congo
29. Sri Lanka
30. Brunei
31. Laos
32. Myanmar

Initial data from the BRCA Challenge is now available at https://brcaexchange.org/

It has long been recognized that there is a need for global integration of data and activities on the genes that predispose for breast and ovarian cancer, particularly BRCA1 and BRCA2. The greatest need is for consistent data collection methodologies and variant interpretation process that operate internationally. In March 2014 at the inaugural Global Alliance for Genomics and Health meeting, Professor Sir John Burn, Human Variome Project Scientific Director for Europe and Africa, proposed a joint initiative of the Global Alliance for Genomics and Health and the Human Variome Project in this area. This collaborative initiative was approved and Sir John was named co-chair of the BRCA Challenge, alongside Stephen Channock from the Laboratory of Translational Genomics at the National Cancer Institute.

To bring focus to the BRCA Challenge, an initial meeting took place in May 2014 at the 5th Biennial Human Variome Project Meeting held at UNESCO headquarters Paris to initiate dialogue between the many groups working on the topic around the world.

 
Major Groups represented at the HVP5 UNESCO meeting were:

• BCAC
• BIC
• CIMBA
• CIRCOS
• ClinGen & ClinVar
• COMPLEXO
• ENIGMA
• Global Alliance for Genomics and Health
• HCI
• Human Variome Project
• InSiGHT
• kConFab
• LOVD Databases
• SCRP
• UMD

The overall aim of the BRCA Challenge is to apply the latest techniques of genetics and genomics to the delivery of health services related to breast cancer. The Challenge will seek to promote the responsible collection, curation, sharing and use of variation data derived from genomic and genetic sequencing in many countries, and create a harmonious data sharing approach between existing databases. This approach will enable the quick and cost-effective delivery of healthcare by providing clinically actionable information in a consistent fashion across the globe.
The BRCA Challenge has three deliverables:

1. Develop population-based assessment of allele frequencies of variants using available sequencing resources
   • Develop a solution for data in existing datasets, including:
     • 1000 Genomes
     • UK10K
     • NHLBI Grand Opportunity Exome Sequencing Project
     • Cancer Genome Atlas
     • International Cancer Genome Consortium
   • Expand the resource to incorporate new NGS data
2. Build federated data collection methodology for pathogenic variants of BRCA1 & BRCA2
   • Build structure for data sharing
     • Begin with BIC/LOVD/UMD/ClinVar
     • Fully integrate ENIGMA/CIMBA & other consortia
     • Invite diagnostic/other data sources
   • Establish consensus on terminology
     • Begin with non-controversial variants (highly pathogenic & benign)
     • Work towards common classification applied to all data available in ‘Federated’ data base
3. Improve and refine penetrance for select mutations
   • Predicated on achieving deliverables 1 & 2
   • Requires extensive planning and collection- primarily of prospective data

The BRCA Challenge will not duplicate or compete with the work of already established groups; rather it will seek to work with all existing activities in the field to add value to and support their work in a sustainable way.
More information on the BRCA Challenge can be found on the website of the Global Alliance for Genomics and Health.