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Myriad Data Shows Reduced Rate of Variants of Unknown Significance for BRACAnalysis, Colaris Tests

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Through a number of evaluation and reclassification techniques, Myriad Genetics has significantly reduced the number of variants of unknown significance identified by its genetic tests for assessing patients' risk for hereditary breast, ovarian, and colorectal cancer, according to data presented at a recent meeting.

At a poster at the European Human Genetics Conference in Nuremberg, Germany, last week, Myriad disclosed the rates at which its BRACAnalysis test and Colaris tests reported variants for which researchers have yet to characterize an association with disease risk. BRACAnalysis gauges mutations in the BRCA 1 and BRCA 2 genes linked to an increased risk of hereditary breast and ovarian cancer. Colaris gauges variants in several genes – MLH1, MSH2, MSH6, PMS2 and EPCAM – associated with heightened risk of developing hereditary colorectal or uterine cancers.

According to Myriad's data, the rate of variants of uncertain significance for the BRACAnalysis test declined from 12.8 percent 10 years ago to 2.9 percent as of this year. Similarly, for the Colaris test, the rate of variants of uncertain significance fell from 10.1 percent in 2005 (when the test only analyzed variants in MLH1 and MSH2), to 6.6 percent in 2012 for the MLH1, MSH2, MSH6, and EMCAM genes. Myriad separately reported that for the PMS2 gene, the rate of variants of uncertain significance is currently 4 percent.

"We have invested tens of millions of dollars and [spent] over 15 years to lower the VUS rate to 2.9 percent in BRCA 1 and BRCA 2," a Myriad spokesperson told PGx Reporter. "Additionally, we have classified over 18,000 mutations, and actively continue to classify variants as they are discovered through testing."

When the BRACAnalysis test was first launched, more than 40 percent of patients' results included one or more variant of unknown significance. "Although the overall rate of VUS has decreased, it is important to note that novel variants are still discovered in these genes," the company stated in its poster, adding that such variants currently occur more frequently when analyzing samples from people of non-European ancestry than for European patients.

The latest data reported by the company show that Myriad has focused on reducing the VUS rate for non-European patients. "Of particular interest is the large decline [in the VUS rate] in the African American and Latin American populations," the company highlighted in its poster. "The dramatic decline in the VUS rate in these ancestries is due to both improved methods for establishing the clinical significance of variants and increased utilization of testing in these populations, which provides more data for analysis."

For instance, for the BRACAnalysis test, the VUS rate in people of Latin American ancestry declined from 26.1 percent in 2002 to 3.9 percent in 2012. For the African population, the rate of VUS declined from 38.6 percent in 2002 to 5 percent in 2012. "As more testing is performed within a given ancestry, the uncertain variant rate within that group is predicted to decline," Myriad stated in its poster.

Myriad noted that interpreting the clinical significance of new variants is a challenging aspect of developing genetic tests. "Interpreting the clinical significance of new variants … requires a costly labor- and data-intensive effort using various lines of evidence to analyze variants of uncertain significance," Myriad said in the poster.

In order to reduce the VUS rate, Myriad employed statistical tools to analyze VUS that co-occurred with mutations associated with the same disease and used a phenotype analysis method that compares the personal or family history of patients with certain VUS to a control population. The company also conducted segregation analysis, evolutionary conservation, and evaluated the literature as ways of reclassifying VUS.

The data reported at ESHG comes at a time when Myriad is trying to expand sales of its genetic testing business throughout Europe. "Current tests available in Europe [for the same indications] have a very high VUS rate, typically 25 percent to 30 percent," a company spokesperson said. "Therefore, many patients are not being provided the information on whether their mutation is harmful or benign."

Myriad officials have projected that the BRACAnalysis, Colaris, and Colaris AP tests will bring in around $100 million in annual revenues in Europe. In reporting its most recent quarterly earnings, Myriad executives highlighted that the company is "ahead of schedule" in setting up shop in European markets and said that the firm is on track to meet its guidance of $59 million in international revenues by fiscal year 2016.

So far, Myriad has set up offices in Germany, Switzerland, France, Italy, and Spain. The revenue from these markets was too small to break out for the three months ended March 31, but Myriad plans to report these figures once its tests gain more traction in these geographies.

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