Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001290705 | SCV001478842 | likely pathogenic | Hereditary thrombocytopenia and hematologic cancer predisposition syndrome | 2021-01-12 | reviewed by expert panel | curation | This missense variant has not been reported in gnomAD (v2 and v3) [PM2]. It has been reported as a germline variant by SCV001203102.1 in a proband (70s) with thrombocytopenia and anemia; however, the germline origins were not confirmed in this case and all other reports of the variant (PMID: 19808697, 22689681, 24523240, 24659740, 25592059, 26273060, 27220669, 27534895, 28659335, 28933735, 30373888, 31649132, 32045476, 32208489, COSMIC). The variant is located at a residue that directly contacts DNA (PMID: 11276260, 12377125, 12393679, 12807882, 19808697, 28231333) and is considered a hotspot residue (PMID: 31648317, 27294619, 23958918), especially from a somatic perspective (PMID: 32208489) [PM1]. Although this variant has not been functionally evaluated, computational evidence supports a deleterious effect of this variant [PP3] and another missense variant at the same residue (i.e. p.R162G) is classified as likely pathogenic by the ClinGen MM-VCEP [PM5_supporting]. In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PM1, PM2, PM5_supporting, and PP3. |
| Invitae | RCV001039570 | SCV001203102 | uncertain significance | Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 | 2023-07-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 162 of the RUNX1 protein (p.Arg162Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is also known as 404G>A, Arg135Lys. ClinVar contains an entry for this variant (Variation ID: 376021). 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 expected to disrupt RUNX1 protein function. Experimental studies have shown that this missense change affects RUNX1 function (PMID: 25840971). 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. |
| Johns Hopkins Genomics, |
RCV000426735 | SCV004239083 | uncertain significance | Acute myeloid leukemia | 2023-08-23 | criteria provided, single submitter | clinical testing | c.485G>A commonly occurs as a somatic variant in association with RUNX1-related disease6, but it has not been reported to occur as a germline variant causative of RUNX1-related disease in the literature, to our knowledge. It is absent from a large population dataset , and has been reported in ClinVar (Variation ID 376021). Two bioinformatic tools queried predict that this substitution would be damaging, but these algorithms have low specificity, especially for predicting gain of function or dominant negative variants. The arginine residue at this position is evolutionarily conserved across all of the species assessed. We consider the clinical significance of c.485G>A in RUNX1 to be uncertain at this time. |
| Database of Curated Mutations |
RCV000426735 | SCV000504774 | likely pathogenic | Acute myeloid leukemia | 2014-10-02 | no assertion criteria provided | literature only |