Submissions for variant NM_001754.5(RUNX1):c.421T>C (p.Ser141Pro)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV005245550	SCV005894754	uncertain significance	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2025-01-15	reviewed by expert panel	curation	NM_001754.5(RUNX1):c.421T>C (p.Ser141Pro) is a missense variant which has a REVEL score ≥ 0.88 (0.97) (PP3). This variant affects a residue within the Runt Homology domain (AA 89-204) but does not affect an established hotspot residue (PM1_Supporting). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). 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: PP3, PM1_supporting, PM2_supporting.
PreventionGenetics, part of Exact Sciences	RCV003397319	SCV004103439	uncertain significance	RUNX1-related disorder	2022-10-24	criteria provided, single submitter	clinical testing	The RUNX1 c.421T>C variant is predicted to result in the amino acid substitution p.Ser141Pro. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003629273	SCV004487636	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2022-12-03	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 141 of the RUNX1 protein (p.Ser141Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. 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 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.