ClinVar Database Evolution and Impact on Potential Pathogenic Germline Variant Reporting from Tumor Comprehensive...

Area of Science:

• Genomic Medicine
• Cancer Genetics
• Bioinformatics

Background:

• Germline genetic testing is underutilized in cancer patients.
• Tumor genomic profiling offers an alternative route to identify high-risk individuals.
• Public databases like ClinVar are crucial for variant classification.

Purpose of the Study:

• To assess the impact of ClinVar database evolution on potential pathogenic germline variant (PPGV) classification.
• To analyze changes in PPGV prevalence and filtering across different ancestral groups over two years.

Main Methods:

• Analysis of ClinVar database changes over a 2-year period.
• Classification of potential pathogenic germline variants (PPGVs) from tumor comprehensive genomic profiling.
• Statistical comparison of variant filtering across diverse genomic ancestry groups.

Main Results:

• ClinVar database showed a 52.2% increase in classified variants across 24 cancer genes.
• PPGV prevalence increased modestly by 0.5% overall.
• Disproportionate filtering of variants was observed in South Asian, admixed American, and African ancestries compared to European ancestry.

Conclusions:

• Database growth improved variant classification, but disparities remain.
• Further improvements in genetic testing access and data sharing are essential to address inequities.
• Ongoing monitoring of variant classification is needed to ensure equitable patient identification.