Variant classification changes over time in the clinical molecular diagnostic laboratory setting.

Area of Science:

• Clinical Genetics
• Genomic Medicine
• Medical Diagnostics

Background:

• Germline genetic testing requires accurate variant classification for patient care.
• Variant classifications include pathogenic, likely pathogenic, uncertain significance, likely benign, and benign.
• Ongoing literature review and evidence accumulation necessitate variant reclassification.

Purpose of the Study:

• To characterize variant reclassifications in Ontario.
• To assess the frequency and nature of variant reclassifications in germline genetic testing.

Main Methods:

• Analysis of DNA samples from hereditary cancer clinics in Ontario (2012-2022).
• Inclusion of patients meeting provincial eligibility criteria for hereditary cancer syndromes or polycystic kidney disease testing.
• Categorization of reclassification events as within or outside the broader category of significance.

Main Results:

• 23.7% of 8075 unique variants were reassessed, with 7.2% reclassified.
• 60.7% of reclassified variants changed outside their broader significance category.
• Most reclassified variants (58.1%) had a significantly different final classification, with a majority downgraded to a more benign status.

Conclusions:

• Variant reclassification is a frequent event.
• A significant proportion of reclassifications represent substantial shifts in variant significance.
• Regular variant reassessment is crucial for maintaining accurate patient care in genetic testing.