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This article is part of the supplement: Proceedings of the 14th Annual Meeting of the Collaborative Group of the Americas on Inherited Colorectal Cancer

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InSiGHT leads in the implementation of the Human Variome Project

Finlay Macrae1234*, Gabriela Moslein15, Richard Cotton36, Rolf Sijmons127, Johan den Dunnen28, Michael Woods1239, Sean Tavtigian102, Mark Jenkins113, Robert Hofstra127 and Robert Haile123

Author Affiliations

1 International Society for Gastrointestinal Hereditary Tumours (InSiGHT),

2 The Human Variome Project,

3 Colon Cancer Family Register,

4 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Parkville, Victoria, Australia

5 HELIOS, St. Josefs-Hospital, Bochum, Germany

6 Genomic Disorders Research Centre, University of Melbourne, Parkville, Victoria, Australia

7 Department of Genetics, University Medical Center Groningen, The Netherlands

8 Department of Human Genetics, Leiden University Medical Center, The Netherlands

9 Disciple of Genetics, Memorial University of Newfoundland, St. John’s, Newfoundland, Canada

10 Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, Utah, USA

11 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Parkville, Victoria, Australia

12 Department of Preventive Medicine, University of Southern California, Los Angeles, California, USA

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Hereditary Cancer in Clinical Practice 2011, 9(Suppl 1):P23  doi:10.1186/1897-4287-9-S1-P23

The electronic version of this article is the complete one and can be found online at:

Published:10 March 2011

© 2011 Macrae et al; licensee BioMed Central Ltd.

This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


With next gen sequencing, the human genome can be sequenced in a few weeks and for a few thousand dollars. Capability is no longer the issue: interpretation is. Assembling information to assist in interpreting the consequences of all base pair changes is the mission of the Human Variome Project (HVP). InSiGHT has collaborated with the HVP, and now, due its coherence and international organization, maintains a Locus Specific Database which is seen as an exemplar for the unfolding of the HVP across the whole genome.


To develop a single comprehensive LSDB relating to MMR and other gene variants predisposing to hereditary GI cancer, permitting the most expert interpretation of the consequence of each variant through a systematic interpretation process.


InSiGHT has appointed a range of committees to oversee a range of activities related to its LSDBs for Hereditary GI cancer. A strong collaboration has emerged between the NCI funded Colon Cancer Family Register, and InSIGHT, extending even further by invitation to all parties interested in MMR repair – the INSILICO MMR consortium. The work is bonded together through the development of the Bayesian Likelihood Ratio for interpretation of VUS, in a transatlantic and Australasian effort.


In the last two years, submissions have increased from 550 to over 13000. The InSIGHT MMR database attracts over 20,000 hits per month from interested parties. All the major MMR databases have been incorporated onto the InSiGHT MMR database (InSiGHT, Newfoundland, functional assay databases) and there have been large depositions of national data (German, French, Canadian, Chinese). A phenotype dataset is being finalized, assisted by the NCI. Functional studies are being assimilated and further developed especially from European expertise. The Bayesian Likelihood Ratio approach to assigning pathogenicity informed by the range of information available relevant to this, is being lead by Sean Tavtigian, sponsored by IARC and now in Utah. The interpretation committees are being supported by the Cancer Council of Victoria. Recently, funding has been secured from the Melbourne based Hicks Foundation for a full time curator of the MMR database. The largest assembly of MMR families ever is associated with the INSILICO consortium, underpinning a range of research opportunities.


InSiGHT is proud of its achievements and leadership for the HVP. Members of the CGA are encouraged to support the InSiGHT databases, so the world can share information on variants for the general good and support of families with MMR mutations.