Submissions for variant NM_001754.5(RUNX1):c.1221C>G (p.Tyr407Ter)

dbSNP: rs914897271

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004699430	SCV005205711	likely pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-08-28	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.1221C>G (p.Tyr407Ter) is a nonsense variant which is predicted to escape nonsense-mediated decay and instead result in truncation of the functionally important C-terminal region, including the transactivation domain, inhibitory domain, and the VWRPY motif (PVS1_Strong). This variant is absent from gnomAD v2/v3/v4 (PM2_supporting), but it has not been reported in patients with RUNX1-related disease. This variant is downstream of c.98 (PM5_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1_strong, PM2_supporting, PM5_supporting.
GeneDx	RCV001584797	SCV001813691	uncertain significance	not provided	2019-02-13	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016; McVean et al., 2012; Exome Variant Server); Nonsense variant predicted to result in protein truncation, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge