Figure 2.

Overview of RUNX1 protein domains, ClinVar-deposited and MM-VCEP curated pilot and COSMIC variants. (A) Schematic of the RUNX1 protein showing its key domains, including the Runt homology domain (RHD); annotation according to MM-VCEP is based on RUNX1 transcript isoform C (NM_001754). (B) Schematic of ClinVar-deposited RUNX1 variants in a one-dimensional line plot showing the current ClinVar five-tier classification; data plotted using proteinpaint from St. Jude.org with data from ClinVar (accessed 6/2019); RHD (purple), and ID (green) are highlighted; numbers indicate amino acid; dotted lines indicate exon boundaries. Some ClinVar-deposited variants (in 5’ and 3’ untranslated regions and large deletions) are not shown. Lollipops representing the variants are colored as follows: PATH (red), LPATH (orange), VUS (grey), LBEN (blue), BEN (purple), CONF (green). MM-VCEP pilot variants¹⁸ are shown in the third row. (C) Three-dimensional structure of the RHD of RUNX1 (blue) complexed to CBFβ (pink) and DNA (orange).⁸² ClinVar RUNX1 variants in this domain (codons 81 to 204 only) are shown using PyMOL, version 2.3.0, as follows: yellow = VUS (n=20), pink = CONF (n=2), orange = LPATH (n=3), red = PATH (n=5); BEN and LBEN variants (n=0). Non-missense variants are not shown. (D) One-dimensional line plot of somatic variants deposited with the Catalog of Somatic Mutations in Cancer (COSMIC: data release 3 Nov. 2018, version 87; https://cancer.sanger.ac.uk/cosmic). MM-VCEP: Myeloid Malignancy Variant Curation Expert Panel; PATH: pathogenic; LPATH: likely pathogenic; VUS: variant of uncertain significance; LBEN: likely benign; BEN: benign; CONF: conflicting interpretations in ClinVar.