ClinVar Miner

Submissions for variant NM_001754.5(RUNX1):c.1219_1221delinsGGGATCGTTCGGA (p.Tyr407fs)

dbSNP: rs2145875208
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel RCV003448403 SCV004176248 likely pathogenic Hereditary thrombocytopenia and hematologic cancer predisposition syndrome 2023-12-09 reviewed by expert panel curation The c.1219_1221delinsGGGATCGTTCGGA (p.Tyr407Glyfs*196) (NM_001754.5) variant in RUNX1 - whose mechanism of disease is established to be loss-of-function - is a protein extension variant that is predicted to escape nonsense-mediated decay but alters a region critical to protein function (transactivation domain, inhibitory domain, and/or the VWRPY motif) (PVS1_Strong). This variant is absent from gnomAD v2, v3, and v4 with at least 20 coverage (PM2_Supporting). Only the somatic variant has been reported in a patient with mixed phenotype acute leukemia (ClinVar SCV001573164.1), but it is of note that other pathogenic/likely pathogenic frameshift alterations in exon 8 have been reported (PMID: 35764482), and other C-terminal frameshift variants have shown loss of transactivation ability and a dominant-negative effect (PMID: 14615365, 19808697, 25840971) (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic 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: PVS1_Strong, PM2_Supporting, and PM5_Supporting. (Version 2; date of approval)
Johns Hopkins Genomics, Johns Hopkins University RCV001376148 SCV001573164 likely pathogenic Acute myeloid leukemia 2021-04-02 criteria provided, single submitter clinical testing

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