ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.967+2_967+5del

dbSNP: rs2056574456
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV001215896 SCV004176275 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2023-12-09 reviewed by expert panel curation NM_001754.5(RUNX1):c.967+2_967+5del is a noncoding variant. This variant was found to co-segregate with disease in multiple affected family members, with seven or more (8) meioses observed in one family/across 1 family (PP1_Strong; PMID: 28240786). Skips exon 8 with in frame del270- 323 and D269A deletion in TAD(PVS1_strong). This variant has been reported in two or three probands (X) meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; PMID: 28240786, doi: 10.1093/ajcp/aqz121.026) (PS4_moderate). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP1_strong, PVS1_strong, PS4_moderate, PM2_supporting
Labcorp Genetics (formerly Invitae), Labcorp RCV001215896 SCV001387664 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2019-09-15 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 28240786). This variant has been observed in a family affected with thrombocytopenia and acute myeloid leukemia (PMID: 28240786). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 8 of the RUNX1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas RCV001215896 SCV004101064 pathogenic Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 2023-11-02 no assertion criteria provided clinical testing

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