Submissions for variant NM_001754.5(RUNX1):c.1118C>A (p.Ser373Ter)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004701227	SCV005205678	likely pathogenic	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-08-28	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.1118C>A (p.Ser373Ter) is a nonsense variant located downstream of c.98 in transcript NM_001754.4 (PM5_Supporting), and is not expected to undergo nonsense-mediated decay. Instead, this variant is predicted to result in a truncated protein lacking a portion of the transactivation domain (TAD), inhibitory domain (ID), and the VWRPY motif, crucial for protein function, affecting positions c.917-c.1440 of the coding region (PVS1_Strong). This variant is absent from all population databases, including gnomAD v2.1.1 and v4.0.0, with at least 20x coverage for RUNX1 (PM2_supporting). It has been observed in a single proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 32165484). The patient, a 14-year-old male, presented with malaise, poor appetite, night sweats, and intermittent fever persisting for approximately one month. Clinical findings included thrombocytopenia (27x10^9/L), and a subsequent bone marrow biopsy revealed acute myeloid leukemia (AML). Additionally, this variant has been reported in sample #393 (PMID: 21531982) in a case diagnosed with Philadelphia chromosome–negative myeloproliferative neoplasm, although the germline origin was not studied. 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, PS4_supporting