Clinically impactful differences in variant interpretation between clinicians and testing laboratories: a...

Area of Science:

• Genetics
• Clinical Diagnostics
• Bioinformatics

Background:

• Accurate variant classification is crucial for diagnosing inherited cardiovascular diseases.
• Discrepancies between clinical interpretation and laboratory findings can affect patient management.
• Existing databases like ClinVar aggregate variant information but may contain conflicting interpretations.

Purpose of the Study:

• To quantify the frequency of disagreements in variant classifications between clinical teams and genetic testing laboratories.
• To analyze the nature and clinical significance of these classification differences.
• To compare clinician-based classifications with laboratory and ClinVar data.

Main Methods:

• Retrospective review of genetic test results from the Stanford Center for Inherited Cardiovascular Disease.
• Comparison of variant classifications provided by ordering clinicians, testing laboratories, and ClinVar.
• Statistical analysis to identify factors associated with classification discordance.

Main Results:

• 18% of laboratory classifications (124/688) differed from clinician classifications.
• The majority of discordant classifications (83%) were clinically significant.
• Clinicians were more conservative in 66% of discordant cases (82/124).
• Clinician classifications showed discordance with ClinVar in 49.1% of cases, compared to 82.5% for testing laboratories.

Conclusions:

• Significant discordance exists between clinical and laboratory variant classifications, similar to inter-laboratory disagreements.
• These discrepancies often have clinical implications, necessitating careful interpretation.
• Clinicians tend to be more conservative in their variant classifications than testing laboratories.