Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004692152 | SCV005196434 | likely benign | Hereditary thrombocytopenia and hematologic cancer predisposition syndrome | 2024-09-11 | reviewed by expert panel | curation | NM_001754.5(RUNX1):c.856C>A (p.Gln286Lys) is a missense variant which is predicted to cause substitution of glutamine by lysine at amino acid 286. The highest population minor allele frequency in gnomAD v2 is 0.00003096 (4/129198 alleles) in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). The germline variant has been reported in a patient with JMML but without features consistent with the RUNX1 phenotypic criteria (PMID: 20955399), and the variant of unclear origin was reported in a patient with cytopenia (PMID: 32241844). In vitro functional studies using HEK293T and HEL cells confirmed the expression of the mutant protein, and the variant demonstrated 80-115% transactivation activity for the CSF1R and MYL9 promoters (PMID: 35026845) (BS3_Supporting). This aligns with the computational predictor, REVEL, which gives a score of 0.152 that is below the threshold of 0.50 and, thus, evidence that does not predict a damaging effect on RUNX1 function; the splice site predictor, SpliceAI, which gives a score of <0.20, also indicates that the variant has no impact on splicing (BP4). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3_supporting, BP4. |
| Labcorp Genetics |
RCV000697732 | SCV000826358 | uncertain significance | Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 | 2024-06-10 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 286 of the RUNX1 protein (p.Gln286Lys). This variant is present in population databases (rs769966051, gnomAD 0.004%). This missense change has been observed in individual(s) with juvenile myelomonocytic leukemia and neurofibromatosis type 1 (PMID: 20955399). ClinVar contains an entry for this variant (Variation ID: 575500). 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 with a negative predictive value of 80%. 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. |
| Baylor Genetics | RCV004569344 | SCV005055496 | uncertain significance | Acute myeloid leukemia | 2023-12-12 | criteria provided, single submitter | clinical testing |