Study finds high degree of discordance between Myriad Genetics and public database in BRCA1 and BRCA2 variant classifications

26 Percent Discordance Rates Observed in Public Databases

Myriad Genetics, Inc., a leader in molecular diagnostics and personalized medicine, today announced that new data comparing BRCA1 and BRCA2 variant classifications between Myriad Genetics and a commonly used public genetic database was published in the journal The Oncologist. A key finding was that the public database provided discrepant variant classifications more than 26 percent of the time, which can introduce uncertainty and diminish patient care.

The study, done in collaboration with William Gradishar, M.D., from the Feinberg School of Medicine at Northwestern University, evaluated 4,250 BRCA1 and BRCA2 variants. Overall, 73.2 percent of variant classifications analyzed were fully concordant, while 26.7 percent were not. Most of the discordant classifications had definitive classifications of pathogenic or benign from Myriad, compared to “variant of uncertain significance” (VUS) classifications in the public database.

“The high degree of discordance seen in this study signals a cautionary note. As a repository of actual patient results, it means that different labs are providing different results to patients for the same genetic mutation. By definition, this means that some patients are receiving incorrect results that may have life-changing or -threatening implications,” said Dr. Gradishar. “The discordance observed within these databases between labs also highlights why public databases do not accommodate the consistent standard of variant classification needed for clinical use. Although efforts are underway to resolve the quality problems within public databases, it is unlikely the issue will be resolved soon and users of public databases likely will continue to encounter discrepancies. At this time, labs should not use public databases in any way in clinical variant classification.”

These findings are consistent with previously published studies. A study by Vail et al. compared the interpretation of more than 2,000 BRCA1/2 variants among five public databases and found substantial disparity of variant classifications among and within publicly accessible variant databases. For VUSs in particular, there is no agreement once the variant is observed in a least four of the five databases in this study. Another study by Balmana et al. assessed conflicting interpretations of genetic variants in the Prospective Registry of Multiplex Testing (PROMPT) and found significant conflicting interpretations of genetic variants in that database. Specifically, among variants entered into the PROMPT registry database with classifications from multiple labs, 26 percent had discrepant classifications; 36 percent of which would affect patient management.  

“There are important clinical implications concerning the high VUS and discordance rates observed in public databases,” said Johnathan Lancaster, M.D., Ph.D., chief medical officer, Myriad Genetic Laboratories. “Dr. Gradishar’s findings reinforce the need for clinical laboratories to invest in meticulous research so that patients can receive the appropriate medical interventions. Over the past 25 years, Myriad has made substantial investments and published more than 8,000 definitively classified variants in peer reviewed publications as well as the details of our variant classification programs to advance the science of variant classification.”  

A recent study published by Kurian et al. showed that many surgeons manage patients with BRCA1/2 VUS the same as patients with BRCA1/2 pathogenic mutations and that half of average-risk patients with VUS undergo bilateral mastectomy. The analysis by Gradishar et al. found that in cases where other commercial laboratories had a VUS classification in the database, 40 to 60 percent of these variants have a definitive classification (pathogenic or benign) by Myriad, which may have helped to avoid many unnecessary surgeries.  

Myriad’s ability to more definitively classify genetic variants stems from its proprietary myVision™ Variant Classification Program and more than 25-years of experience.

“Variant classification is a complicated endeavour and multiple studies have shown that it matters when patients are tested by laboratories that have not invested in the necessary research but are dependent in part on public databases,” said Dr. Lancaster. “Myriad is the unquestioned leader in genetic testing for hereditary cancers. Over the last 25-years, Myriad has delivered millions of test results, which means the myVision program is based on the largest and most robust database in the industry to identify, classify, and assign clinical significance to genetic variants.”

Key features of the myVision variant classification program include:

  • Classification by industry-leading experts. The Myriad Variant Classification Program consists of a large and diverse team of scientists with hundreds of years of cumulative experience who determine the clinical significance of variants.
  • Innovative and exclusive technologies. myVision employs cutting-edge statistical techniques developed after testing more than 500,000 patients. And, we continue to evaluate variants over time as new data and technology become available.
  • Dramatically declining VUS rates. Myriad has reduced the BRCA1/2 VUS rates from 40 percent to 1.6 percent, dramatically lower than any other laboratory.
  • Reviewed by the U.S. Food and Drug Administration as a part of the BRACAnalysis CDx premarket approval submission.
  • Lifetime commitment to every patient tested. When a VUS is reclassified as clinically actionable in the future, an amended report will be made available to the patient, which is unique to Myriad’s program.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News-Medical.Net.
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