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

Abstract

Although recommended for a high percentage of patients with cancer, germline genetic testing is widely underutilized. Classification of pathogenic variants of potential germline origin (potential pathogenic germline variants; PPGV) from tumor comprehensive genomic profiling enables identification of patients and families with high cancer risk via an alternative pathway to clinical germline evaluation. Foundation Medicine utilizes evidence in the ClinVar database to classify PPGVs. We investigated the impact of ClinVar database evolution over a 2-year period on the classification of PPGVs across solid tumors. Substantial growth in the database (a 52.2% increase in classified variants across 24 cancer susceptibility genes) yielded a modest increase in PPGV prevalence (+0.5% across tissue and liquid biopsies combined). Whereas filtering of PPGVs because of insufficient evidence for pathogenic classification decreased across all ancestry groups, disproportionate filtering of variants in patients of South Asian (40.0%), admixed American (36.5%), and African (36.3%) versus European genomic ancestry (33.8%, P ≤ 0.01 for all comparisons) was still observed. Continuing improvements to genetic testing access and data sharing are needed to mitigate disparities.

Significance: Whereas efforts to improve data sharing have led to the growth of public genomic databases (e.g., ClinVar) over time, underutilization of genetic testing and persistent racial and ethnic disparities are limitations that continue to affect these important resources.