Background: The presence of benign variants or passenger mutations in driver genes from public databases is one of the well-documented limitations when reporting clinical actionability of somatic mutations. However, our understanding on classification and interpretation of somatic mutations is far from being perfect. The aim of this study is to investigate the frequency of benign variants from the Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census (CGC) and the interpretation concordance of OncoKb variants in depth.
Methods: We used a total of 339,425 somatic mutations in CGC genes registered in the COSMIC. Multiple databases incluing CIViC and Gene Drug Knowledge database and in silico tools were used to interpretate the clinical actionability of the mutations. All mutations were reanalyzed by a four-tiered system based on the consensus recommendation of the Association for Molecular Pathology (AMP), American Society of Clinical Oncology, and College of American Pathologists, and compared to OncoKb classification.
Results: The frequency of benign or likely variants, which were categorized as Tier IV variants according to AMP guideline, in the COSMIC CGC was 1% (4,200/339,425) of the mutations. Although 75% (3,129/4,200) of the Tier IV variants were flagged as polymorphism, while there was no warning sign in remaining 25% of benign variants. In addition, 70% (2,952/4,200) of the Tier IV variants were recurrently observed in at least two samples. Overall concordance of actionable mutations between AMP classification (Tier I or Tier II) and OncoKb (Oncogenic or likely oncogenic) were 88% (3,118/3,565) of variants studied.
Conclusions: Interpretation and reporting of somatic mutations in cancer databases need to use with caution. We found that significant number of somatic mutations registered in COSMIC CGC may not be clinically-actionable mutations. This study could be a good starting point for in-depth review of somatic mutation information essential for precision oncology.