Abstract 1200: COSMIC cancer mutation census: Classifying somatic coding variants by their potential to drive cancer

Abstract Somatic mutations accumulate in cells throughout their life. Most of them do not bring any negative effect. However, certain mutations change protein behaviour, structure, or level of expression. More importantly, some mutations are known to initiate and drive oncogenic transformation. These mutations often make good therapeutic targets but recognising this small subset in a cancer sample is a major challenge. The average cancer cell carries a life-long baggage of somatic mutations, and the mutational process is sped up in these cells through genomic instability (one of the hallmarks of cancer). As a result, there are hundreds of thousands of variants of unknown significance identified through sequencing of cancer DNA. COSMIC Cancer Mutation Census (CMC) answers this challenge by identifying coding mutations with a potential to drive cancer. This is achieved by combining manually curated information regarding cancer genes and genetic variants with data on variant frequencies in cancer and non-cancer populations, and algorithmic evaluation of variant significance. It applies a simple and transparent set of rules to the whole set of coding mutations in COSMIC to identify variants with the highest potential of clinical relevance. In current version (v95, November 2021) the CMC describes 4.7 million somatic variants and segregates them into four tiers. Tier 1 is the highest confidence set. This set includes 1558 mutations that are found in Cancer Gene Census genes and are also described as pathogenic in cancer by ClinVar. Tiers 2 and 3 contain variants with less extensive evidence of involvement in carcinogenesis. The dN/dS algorithm is used to include variants that are under positive selection in cancer cells. Finally, mutations without evidence for driving cancer are classified as Tier 4. In addition to this classification, CMC integrates and presents the information used to prioritise variants, including their frequencies in various cancer types (COSMIC), germline frequencies (gnomAD), ClinVar annotations, dN/dS analysis results, and nucleotide and amino acid conservation. Data can be accessed and scrutinised through a dedicated website at https://cancer.sanger.ac.uk/cmc. Citation Format: Zbyslaw Sondka, Bhavana Harsha, Helder Pedro, Nidhi Bindal Dhir, Charlie Hathaway, Sumodh Nair, Doron Sondheimer, Simon A. Forbes. COSMIC cancer mutation census: Classifying somatic coding variants by their potential to drive cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1200.