Submissions for variant NM_001754.5(RUNX1):c.1051G>A (p.Gly351Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV003409974	SCV004123219	uncertain significance	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2023-11-13	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.1051G>A (p.Gly351Ser) is a missense variant. This variant is completely absent from all population databases with at least 20x coverage for RUNX1 in gnomAD v2.1.1 and v3.1.2 (PM2_supporting). This missense variant has a REVEL score < 0.50 (0.16) and SpliceAI score is <= 0.20 (0) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002938885	SCV003270448	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2022-09-30	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 351 of the RUNX1 protein (p.Gly351Ser). This variant is not present in population databases (gnomAD no frequency). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RUNX1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.