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)