Fig. 2: Representation of genomic variants across interpretation knowledgebases.

a, UpSet plot⁴⁶ of variants across six cancer variant interpretation knowledgebases (KBs). Sets of variant interpretation knowledgebases with shared variants are indicated by colored dots in the lower panel, with color indicating set size (for example, yellow dots indicate only the single designated knowledgebase in the set, green dots indicate two knowledgebases in the set, etc.). Objects are attributed to the largest containing set; thus, a variant described by all six knowledgebases is attributed to the dark blue set with eight variants. b, Pie chart visualizing overall uniqueness of variants, with categories indicating the number of knowledgebases describing each variant. Nearly 77% of variants are unique across the knowledgebases, with only 0.2% ubiquitously represented. The eight variants present in all six knowledgebases are listed on the right. c, A comparison of element uniqueness across knowledgebases. Despite having the greatest degree of overlap across all elements, approximately 61% of genes are unique across the knowledgebases. Literature cited to support interpretations has the smallest degree of overlap across all elements, with 83% of publications remaining unique across the knowledgebases. *Drugs are not evaluated for PMKB, which does not formally represent this concept. d, Multiple syntactically valid representations of an identical protein product can lead to confusion in describing the change in the literature and in variant databases. The wild-type protein sequence (dark blue with orange lettering) is represented for ERBB2 (top). Two (of many) possible representations of an inframe insertion (orange with dark blue lettering) are shown (bottom). A nonstandard HGVS expression describes a five-amino-acid insertion replacing one glutamate residue (middle). At the bottom, the HGVS standard representation shows an identical protein product from a four-amino-acid duplication. A search for one representation against a database with another (nonoverlapping) representation may lead to omission of a clinically relevant finding.