Variant classification changes over time in BRCA1 and BRCA2.

Area of Science:

• Genetics
• Molecular Diagnostics
• Bioinformatics

Background:

• BRCA1 and BRCA2 (BRCA1/2) gene variants are critical in hereditary cancer risk assessment.
• Accurate classification of BRCA1/2 variants is essential for patient diagnosis and management.
• Variant interpretation can evolve with new scientific evidence and updated guidelines.

Purpose of the Study:

• To document BRCA1/2 variant reassessments and reclassifications at a Canadian molecular diagnostics laboratory from 2012 to 2017.
• To compare the laboratory's variant classifications with data submitted to ClinVar.
• To assess the impact of variant reclassification on patient care and data sharing practices.

Main Methods:

• Utilized a standardized variant assessment tool adhering to ACMG/AMP guidelines.
• Tracked variant assessments and reclassifications in an in-house database.
• Shared variant data through the Canadian Open Genetics Repository and submitted to ClinVar for inter-laboratory comparison.

Main Results:

• Over 1200 BRCA1/2 variants were identified between 2012 and 2017.
• Approximately 33% of variants were reassessed, and 12% were reclassified, with most downgrades.
• Significant discordance (40.4%) was observed between laboratory submissions and ClinVar data.

Conclusions:

• BRCA1/2 variant classifications are dynamic and subject to change over time.
• Reclassification of variants poses challenges for patient re-contact and genetic counseling.
• Enhanced data sharing is crucial for improving variant interpretation accuracy and ensuring appropriate patient care.