Changes in classification of genetic variants in BRCA1 and BRCA2

Area of Science:

• Genetics
• Oncology
• Bioinformatics

Background:

• Classifying variants of unknown significance (VUS) in BRCA1 and BRCA2 is crucial for hereditary breast and ovarian cancer risk assessment.
• Accumulating evidence influences the clinical relevance of VUS, necessitating periodic re-evaluation.
• Previous studies have documented classification changes, highlighting the evolving nature of variant interpretation.

Purpose of the Study:

• To analyze changes in the classification of genetic variants within the BRCA1 and BRCA2 genes.
• To update the classification status of variants previously categorized as VUS.
• To assess the direction and extent of classification changes over a defined period.

Main Methods:

• Database search of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC).
• Inclusion of classification changes recorded between 2015 and 2017.
• Focus on variants initially classified as VUS (Class 3) and their reclassification.

Main Results:

• In BRCA1, 25% (2/8) of VUS were reclassified to likely benign (Class 2) or benign (Class 1).
• In BRCA2, 50% (16/32) of VUS were reclassified to likely benign (Class 2) or benign (Class 1).
• No pathogenic variants (Class 4 or 5) were reclassified, and no VUS were upstaged to higher clinical significance.

Conclusions:

• All reclassified variants in the study cohort were downstaged to indicate no clinical significance.
• Expert panels confirmed the downstaging of variants.
• Hereditary breast and ovarian cancer prevention strategies for families with VUS should rely on pedigree analysis rather than VUS presence alone.