ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.620G>A (p.Arg207Gln)

dbSNP: rs1229231012
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV003405246 SCV004123181 uncertain significance Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2023-11-13 reviewed by expert panel curation The c.620G>A (NM_001754.5) variant in RUNX1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 207 (p.R207Q). The highest population minor allele frequency in gnomAD v2 is 0.000008899 (1/112370 alleles) in the non-Finnish European population. The likely germline variant has been reported in an 81yo male with AML and a negative family history (PMID: 23753029), but additional reports of the variant are of either unclear origin (PMID: 29146900; PMID: 36436542) or somatic origin (PMID: 31772163; PMID: 32619037; PMID: 36219880; PMID: 25790293; PMID: 29420467; PMID: 30072744; DepMap Portal/CCLE). The computational predictor REVEL gives a score of 0.801, which is neither above nor below the thresholds predicting a damaging or benign impact on RUNX1 function. The splice site predictor SpliceAI indicated that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a VUS 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: none
Invitae RCV001045813 SCV001209687 uncertain significance Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2023-09-13 criteria provided, single submitter clinical testing Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RUNX1 protein function. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 207 of the RUNX1 protein (p.Arg207Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with acute myeloid leukemia (PMID: 23753029). ClinVar contains an entry for this variant (Variation ID: 843240). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sema4, Sema4 RCV002259071 SCV002535871 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-10 criteria provided, single submitter curation
Baylor Genetics RCV003467744 SCV004209846 uncertain significance Acute myeloid leukemia 2023-09-18 criteria provided, single submitter clinical testing

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