Variations on a Theme: Analyzing Unclassified BRCA1 and BRCA2 Variants

Principal investigator: Sean Tavtigian, PhD

Mutations in the BRCA1 and BRCA2 genes are well-known to increase the risk of breast and ovarian cancer in people who carry them. Like all genes, they consist of basic parts strung together in a certain order, like letters in a word. Some of the "misspellings" of BRCA1 and BRCA2 have been well analyzed and are known to increase cancer risk. Scores of other variations in these genes have been observed but not yet analyzed. These variations present a frustrating issue for genetic counselors and the patients they serve.

Sean Tavtigian, PhD

"Genetic testing on patients with a family history of breast or ovarian cancer may show a variation known to cause disease, and we know what to do for these patients and their family members," says Tavtigian. "But when testing finds an 'unclassified variant' [for which the effect on cancer risk is unknown], reporting the results to patients only increases their anxiety and uncertainty."

Tavtigian created an open-access database, which means researchers, physicians, genetic counselors—even patients—can retrieve information from it. The database is currently operated from the International Agency for Research on Cancer in Lyon, France. Over the next two years, the agency will turn over operation of the database to Huntsman Cancer Institute, along with a similar database for colon cancer susceptibility genes. Tavtigian, along with HCI investigator David Goldgar, PhD, and genetic counselor Amanda Gammon, MS, CGC, worked in an international collaboration to classify most of these variations. A peer-reviewed article describing the classification project was e-published in November 2011 and appears in print in the January 2012 issue of the journal Human Mutations.