Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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, |
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 |