Molecular testing for the BRCA1 and BRCA2 Ashkenazi Jewish founder mutations: a report on the College of American Pathologists proficiency testing surveys.

purposeThe purpose of this study was to analyze laboratory performance on proficiency testing surveys offered jointly by the College of American Pathologists/American College of Medical Genetics and Genomics biannually for the three common Ashkenazi Jewish founder mutations in the BRCA1 and BRCA2 genes.

methodsSurvey responses were analyzed for accuracy of genotype determination and the associated clinical interpretation. Data on an individual laboratory's participation over time, number of samples tested, turnaround time, and test methodology were also reviewed.

resultsBetween 2003 and 2012, 23 US laboratories and 39 international laboratories participated. There were six genotyping errors, with a corresponding analytical sensitivity of 99.0% (479/484 challenges; 95% confidence interval: 97.6-99.7%) and an analytic specificity of 99.9% (870/871; 95% confidence interval: 99.4-99.9%). Among the 1,325 clinical interpretations, 92.5% (1,226/1,325; 95% confidence interval: 91.0-93.9%) matched the intended response. Most of the 99 discrepancies-81% (80/99)-incorrectly interpreted the risk for a negative test result as having a lifetime risk of breast cancer "that is the same as that in the general population" instead of "that cannot be determined without BRCA mutation testing of the affected relative."

conclusionClinical laboratories demonstrated excellent analytical sensitivity and specificity. The clinical interpretation requires additional education, focusing on the clinical interpretation of negative test results for these three mutations.