Increased access to genetic testing enables oncologists to categorize genetic variants in ways that can suggest more effective treatment plans for their patients. However, updated information regarding the effects of genetic variants can require reassessing their significance for patients, a study published in the Journal of the American Medical Association has shown.

In this retrospective study of genetic testing results from 2006 to 2016 at a commercial laboratory, 24.9% of all variants that had originally been deemed of uncertain significance were reclassified.

From the 1.45 million people examined in this study, 56.6% of whom had a history of cancer, 1.67 million initial genetic reports were generated. A total of 59,955 of the reports were later amended due to reclassification of variants.

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The rate of reclassification to variants of uncertain significance was low from those initially classed as pathogenic/likely pathogenic (0.7%) and from those initially classed as benign/likely benign (0.2%). Among unique variants that were initially classed as variants of uncertain significance, 7.7% (n=2048) were reclassified, with 91.2% of those reclassified as benign/likely benign (n=1867) and 8.7% as pathogenic/likely pathogenic (n=178).

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In a subset of data that underwent chart review, genetic variants that were downgraded from pathogenic/likely pathogenic to variants of uncertain significance were found in BRCA1, BRIP1, and TP53 genes. Variants in the subset that were reclassified from uncertain to pathogenic/likely pathogenic significance came from BRCA1, BRCA2, CDH1, CHEK2, MLH1, and MSH6 genes.

This report considered results from one laboratory, so the authors noted that results from other laboratories should be analyzed, in addition to evaluation of clinical effects of any variant classifications.


Mersch J, Brown N, Pirzadeh-Miller S, et al. Prevalence of variant reclassification following hereditary cancer genetic testing. JAMA. 2018;320(12):1266-1274.