Submissions for variant NM_001754.5(RUNX1):c.735del (p.Thr246fs)

dbSNP: rs2146075448

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV003448451	SCV004176234	pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2023-12-09	reviewed by expert panel	curation	The NM_001754.5(RUNX1):c.735del (p.Thr246ArgfsTer8) is a frameshift variant in a gene in which loss-of-function is an established mechanism (Frameshift (+1); c.98-c.779 as per VCEP specifications) (PVS1). At least 2 probands with RUNX1-phenotypic criteria have been reported (PS4_moderate). Cosegregation with disease in multiple affected family members (4 meiosis across 2 families) have been observed (PP1). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). This frameshift variant is downstream of c.98 in transcript NM_001754.4 (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PS4_moderate, PP1, PM2_supporting, PM5_supporting.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002254233	SCV002525484	likely pathogenic	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1		no assertion criteria provided	clinical testing