An international team of researchers has developed, calibrated, and validated a novel tool for identifying the genetic changes in Lynch syndrome genes that are likely to be responsible for causing symptoms of the disease. The results were published by Drost et al in Genetics in Medicine.
Lynch syndrome is a hereditary condition that results in higher rates of colon, endometrial, and other cancers. If unmanaged, individuals with Lynch syndrome have a 75% lifetime risk of developing colorectal cancer—it is believed that approximately 5% of all colorectal cancer cases are associated with this syndrome.
The team used a laboratory test previously developed by the group of Niels de Wind, PhD, Associate Professor of Human Genetics at the Leiden University Medical Center in The Netherlands, to characterize genetic changes associated with disease risk. The lab test, called the Cell-free in vitro MMR Activity (CIMRA) assay, improves classification of variants of uncertain significance in Lynch syndrome.
In the current study, the test was thoroughly calibrated and validated, such that its results could now be integrated with computer-based modeling and clinical data. The CIMRA assay alone correctly classified 65% of variants, with only 3% discordant classification. Bayesian integration with in silico predictions of pathogenicity increased the proportion of correctly classified variants to 87%, without changing the discordance rate. Interlaboratory results were highly reproducible.
“A key point is that we believe the accuracy of the tool combining the CIMRA test with the previously published computational analysis to be about 97%, making it appropriate for clinical use,” said researchers. Dr. de Wind added that the work “represents a new pinnacle in the classification of genetic variation.”
The authors believe that routine utilization of their methods will dramatically increase the rate of risk classification for genetic changes that previously were poorly understood. Moreover, this calibration strategy provides a template for the development, validation, and calibration of reliable strategies for the diagnostic assessment of other hereditary cancer predisposition syndromes and genetic disorders.
Disclosure: The study was funded by the National Institutes of Health, National Cancer Institute, the Huntsman Cancer Foundation, and the Dutch Digestive Foundation. The study authors’ full disclosures can be found at nature.com.
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