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Study Questions Validity of Genetic Variant Classification in Public Databases


A study published in The Oncologist concluded that discrepant variant classification in public databases can introduce uncertainty and diminish patient care.

Can we trust gene variant information generated by public databases? A study published in The Oncologist concludes that discrepant variant classification in public databases can introduce uncertainty and diminish patient care.

Researchers at Northwestern University compared variant classifications obtained from a reference laboratory and from the public database ClinVar, a public archive of reports on human genotypic and phenotypic variations. Being a open access database, researchers can freely submit their clinical observations on genetic information on patient samples and the observed phenotype resulting from the genetic variance. Following processing of the submitted information, ClinVar makes the data available to interactive users as well as those wishing to use ClinVar in daily workflows and other local applications.

For their study, the researchers at Northwestern obtained variant classifications of BRCA1 and BRCA2 from ClinVar, which were then compared with the classification by a reference laboratory. Concordance and discordance were determined for variants whose ClinVar entries were of the same pathogenicity—pathogenic, benign, or uncertain. In case of a conflict, partial concordance was assumed “if ≥1 of the listed classifications agreed with the reference laboratory classification,” the authors note.

Of the more than 4200 unique BRCA variants that were studied, less than three-fourths (73.2%) were fully concordant, and 12.3% were partially concordant. A majority of the 14.5% variants with discordant classifications had a definitive classification (pathogenic or benign) from the reference laboratory compared with an uncertain classification in ClinVar.

Such discrepancy can have far-reaching consequences on treatment decisions, if physicians use such databases to interpret genetic test results on their patients’ tumor samples. According to the authors, a great deal of expertise and time investment may be needed for clinicians to research these discordant classifications and “calls into question the practicality of checking all test results against a database.” They also warn against using such databases for clinical interpretation of test results.

“The high degree of discordance seen in this study signals a cautionary note," senior study author William Gradishar, MD, said in a press release. "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.”


Gradishar W, Johnson K, Brown K, Mundt E. Manley S. Clinical variant classification: a comparison of public databases and a commercial testing laboratory [published online April 13, 2017]. Oncologist. pii: theoncologist.2016-0431. doi: 10.1634/theoncologist.2016-0431.

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