ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.330G>C (p.Lys110Asn)

dbSNP: rs1569084082
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV003448333 SCV004176261 likely pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2023-12-09 reviewed by expert panel curation The c.330G>C (NM_001754.5) variant in RUNX1 is a missense variant predicted to cause substitution of lysine by asparagine at amino acid 110 (p.K110N). This variant involves one of the hotspot residues that is defined as a mutational hotspot by the ClinGen MM-VCEP (PMID: 31648317; PMID: 10404214; PMID: 10620014; PMID: 11257229; PMID: 26010396) (PM1). The variant is absent from gnomAD v2, v3, and v4 with at least 20x coverage (PM2_Supporting). The variant has been reported in 4 individuals with AML, but variant origin is unclear (PMID: 10068652; PMID: 27288520; PMID: 31772163; PMID: 32696696) (PS4_Supporting is not met); the somatic variant has been reported in AML (PMID: 29472724), gMDS (PMID: 31772163), and TCGA bladder cancer (COSMIC ID: COSV55875639/cBioPortal) samples. The variant in a transactivation assay using the M-CSF promoter exhibited a 70% reduction; the mutant protein was also unable to bind DNA whether or or not in the presence of the CBFβ subunit, without affecting CBFβ heterodimerization and nuclear localization (PMID: 10068652; PMID: 11830488) (PS3). Additional studies of the mutant protein in mouse bone marrow cells showed that it decreases the ratio of erythroid to myeloid colonies, results in immortalization of cells, and the accumulation of myeloblasts and dysplastic progenitors (PMID: 17234761). Similarly, the computational predictor REVEL gives a score of 0.884, which is above the threshold of 0.88 (evidence that correlates with impact to RUNX1 function), and the splice site predictor SpliceAI indicated that the variant has no impact on splicing (PP3). In summary, this variant meets the criteria to be classified as a likely pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PS3, PM1, PM2_Supporting, and PP3. (Version 2; date of approval)
PreventionGenetics, part of Exact Sciences RCV000680404 SCV000807775 pathogenic not provided 2018-07-12 criteria provided, single submitter clinical testing

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