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Research Department of Genetics
University Medical Center Groningen

Better understanding of DNA findings in Familial Bowel Cancer

24 December 2013

An international consortium of over 45 medical scientists have combined their expertise to study hereditary DNA sequence changes in the most common form of hereditary bowel cancer called Lynch Syndrome.

This has enabled clinicians to determine if such mutations are damaging, and capable of deadly consequences, or whether they are a simple DNA variation of no consequence. But this is a challenge that faces clinicians and scientists across all genetic diseases, as they address the tsunami of DNA variation data that is emerging from high-tech, rapid-throughput sequencers.

The model, published in a paper this week in the internationally renowned journal Nature Genetics (see below) , means that it will be easier to offer testing to thousands of families throughout the world who otherwise are left with uncertainty about their genetic risk.

Familial bowel cancer, like common but incidental bowel cancer, can often not be detected until symptoms of the disease appear, and without genetic testing to enable focused and frequent surveillance on these high risk family members, it can have devastating consequences on generations of the same family.

While the study provides definitive interpretation relating to variants previously not well understood for their risk they carry for bowel cancer, the model described in the paper has much wider implications into how best to pick up all types of rare genetic diseases, including other cancers, neurological conditions, and blood diseases.

According to Professor Rolf Sijmons of the Department of Genetics of the University Medical Center Groningen, of those people under 50 years of age diagnosed with bowel cancer who have genetic testing to identify a familial risk, more than 1 out of 10 have Lynch Syndrome due to a damaging mismatch repair gene mutation responsible for the syndrome.

Others may have normal DNA test results and do not have a high familial risk for the disease. However, a significant number of individuals have a range of genetic variants that may or may not indicate that a family is at risk – these families are left in limbo, with clinicians being unable to be certain of their genetic diagnosis or cancer risk.

All this genetic data has been centralized into an international database hosted by InSiGHT, the International Society for Gastrointestinal Hereditary Tumours. To date, 3,500 variants from mostly unrelated families have been considered and assigned a status in the InSiGHT database as to whether they are damaging or not (or despite best efforts, still uncertain) (

Professor Sijmons, who participated in the project, said the InSiGHT group encourages any clinicians worldwide to submit genetic data related to bowel cancer sufferers.

“In the last 18 months, the 45 international experts have conducted regular teleconferences to discuss new information submitted to the database,” he said.

“Each genetic mutation is analyzed by at least two to three members separately and then by the entire committee to determine how it should be classified in the database: as damaging or benign.”

“The model – using the expertise of international clinicians with a particular knowledge of a rare disease – essentially turns indecipherable (sequencing) data into relevant knowledge that can have a real clinical benefit.”

“For example, we may have a family in the Netherlands with only a few members who have a particular genetic mutation and some indication of bowel disease. But we have no idea whether we should test the whole family to predict their cancer risk and help them take preventive measures.”

“However, our colleagues in other countries may have seen the same mutation in much larger families, allowing them to determine that the variant does indeed cause cancer. So, through this collaborative effort, and the InSiGHT process which considers additional information as well, we can be confident of our counseling advice to our Dutch family, and offer them testing for the mutation.”

Professor Sijmons added that this experience would be of enormous benefit to other medical researchers working in the field of genetics of rare diseases.

“This has the potential to not only cut the cost of treating cancers that occur in these family members through early diagnosis, but it also has the capacity to save lives,” Professor Sijmons said.

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

BA Thompson et al., Nature Genetics, 22 Dec 2013 PubMed


The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases.

Last modified:14 December 2023 08.16 a.m.

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