Marc Greenblatt, MD and Emily Nadeau, PhD
With the advancement of personalized medicine, DNA testing to assess genetic risk factors for cancer has become common. However, these tests often result in the detection of variants of unknown significance, a genetic variation for which the clinical significance is unknown. Variants of unknown significance pose a clinical challenge in that they cannot be classified as pathogenic (disease associated) or benign. A series of new papers by Marc Greenblatt, MD, postdoctoral researcher Emily Nadeau, PhD, and colleagues, published in Genome Biology, Genetics in Medicine, the American Journal of Human Genetics (AJHG), and a commentary in Nature Genetics, advances the work of interpreting genetic variation from two perspectives. First, how to use computational tools to interpret variations, and second, how to apply evidence to a specific important hereditary cancer syndrome, Familial Adenomatous Polyposis (FAP).
Drs. Greenblatt and Nadeau work closely with the Sequence Variant Interpretation team of the NIH-funded “ClinGen” project, which supports the refinement of guidelines for interpreting sequence variants based on evolving research. In their recent publication in Genetics in Medicine (Stenton et al.), they highlight how computer algorithms and predictive tools can be applied to patient genome sequencing to realistically predict the number of pathogenic and benign variants. In the Nature Genetics commentary (Karchin et al.), the authors discuss the need for increased transparency in the development and testing of variant effect predictive algorithms to optimize the reliability of predictions. The Genome Biology publication represents Dr. Greenblatt’s longstanding collaboration with the Critical Assessment of Genome Interpretation (CAGI) Consortium which brings together computational, laboratory, and clinical genetics communities. The publication reports on the recent progress of the Consortium in advancing computational prediction of genetic variants.
An excellent example of the power of a systemic approach to genetic variant classification is the work Drs. Greenblatt and Nadeau have conducted in collaboration with ClinGen’s Polyposis/Colon Cancer Variant Curation Expert Panel (VCEP), which Dr. Greenblatt leads. In their recent Genetics in Medicine publication (Spier et al.), the authors report a set of new rules to classify variants in the APC gene, a gene in which some mutations are known to increase the risk of Colon Cancer. In addition, work published in the AJHG publication (Yin et al.) examined over 10,000 variants in the APC gene, reducing the number of variants of unknown significance by 37%, with the majority classified as benign. These changes will directly impact the clinical care of patients who have identified variants in the APC gene.
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