Clinical variant classification: A comparison of public databases and a commercial testing laboratory

William Gradishar*, Karianne Johnson, Krystal Brown, Erin Mundt, Susan Manley

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


Background. There is a growing move to consult public databases following receipt of a genetic test result from a clinical laboratory; however, the well-documented limitations of these databases call into question how often clinicians will encounter discordant variant classifications that may introduce uncertainty into patientmanagement. Here, we evaluate discordance in BRCA1 and BRCA2 variant classifications between a single commercial testing laboratory and a public database commonly consulted in clinical practice. Materials and Methods. BRCA1 and BRCA2 variant classifications were obtained from ClinVar and compared with the classifications from a reference laboratory. Full concordance and discordance were determined for variants whose ClinVar entries were of the same pathogenicity (pathogenic, benign, or uncertain). Variants with conflicting ClinVar classifications were considered partially concordant if≥1 of the listed classifications agreed with the reference laboratory classification. Results. Four thousand two hundred and fifty unique BRCA1 and BRCA2 variants were available for analysis. Overall, 73.2% of classifications were fully concordant and 12.3% were partially concordant. The remaining 14.5% of variants had discordant classifications, most of which had a definitive classification (pathogenic or benign) from the reference laboratory compared with an uncertain classification in ClinVar (14.0%). Conclusion. Here, we show that discrepant classifications between a public database and single reference laboratory potentially account for 26.7% of variants in BRCA1 and BRCA2. The time and expertise required of clinicians to research these discordant classifications call into question the practicality of checking all test results against a database and suggest that discordant classifications should be interpreted with these limitations in mind.

Original languageEnglish (US)
Pages (from-to)797-803
Number of pages7
Issue number7
StatePublished - Jul 2017


  • BRCA1
  • BRCA2
  • Genetic testing
  • Public databases
  • Variant classification

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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