Submissions for variant NM_001754.5(RUNX1):c.422C>T (p.Ser141Leu)

dbSNP: rs1601516118

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Myeloid Malignancy Variant Curation Expert Panel	RCV004693308	SCV005196568	uncertain significance	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome	2024-07-17	reviewed by expert panel	curation	NM_001754.4(RUNX1):c.422C>T (p.Ser141Leu) is a missense variant which is completely absent from gnomAD with a mean coverage of at least 20X (v2 and v3). REVEL score = 0.906, which is higher than the v2 threshold of 0.88. SpliceAI doesn't predict any significant splicing impact (Δ scores ≤ 0.20). Not located at a hotspot (R107, K110, A134, R162, R166, S167, R169, G170, K194, T196, D198, R210, R204), but within residues 89-204. The germline variant has been reported in a male patient with CMML diagnosed at 67 years and antecedent thrombocytopenia (PMID: 34028844), and in a patient with myeloid disease that may have also had a history of thrombocytopenia (Nielsen et al., 2016, ASH Abstract 602/DOI: 10.1182/blood.V128.22.3926.3926). The variant has also been reported in several patients with MDS or CMML (PMID: 19282830; PMID: 20880116; PMID: 24030381; PMID: 25840971; PMID: 29515765), AML (PMID: 16627249; PMID: 17485549; PMID: 24923295; PMID: 27288520; PMID: 32855275), AML-MRC (PMID: 31728617), chronic neutrophilic leukemia (PMID: 31844143), and myeloid sarcoma (PMID: 31866570), but germline origin is unclear. Germline origin was also unclear in 3 patients tested at Invitae - 2 of whom were possibly mosaic and 1 of whom was heterozygous (although blood was limited) - without RUNX1-related phenotype. Finally, the somatic variant has been reported in a TCGA AML (PMID: 23634996/COSMIC ID: COSV55867675/cBioPortal), 2 MDS (PMID: 24047651), a urothelial carcinoma (PMID: 25096233/cBioPortal), and cecal carcinoma (PMID: 28481359/cBioPortal). 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: PM2_supporting, PM1_supporting, PP3, and PS4_moderate
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804289	SCV000944192	uncertain significance	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1	2023-08-07	criteria provided, single submitter	clinical testing	This variant is also known as c.341C>T (p.Ser114Leu). This missense change has been observed in individual(s) with chronic myelomonocytic leukemia (CMML). However, it is uncertain if the variant is of germline or somatic origin (PMID: 25840971, 34028844). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 141 of the RUNX1 protein (p.Ser141Leu). ClinVar contains an entry for this variant (Variation ID: 649370). 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. Experimental studies have shown that this missense change affects RUNX1 function (PMID: 25840971, 31048839). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RUNX1 protein function.
GeneDx	RCV004723214	SCV005334377	uncertain significance	not provided	2023-09-18	criteria provided, single submitter	clinical testing	Observed in an individual with myelodysplastic syndrome; however, germline status was not confirmed (Tsai et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.341C>T, p.Ser114Leu; This variant is associated with the following publications: (PMID: 34028844, 31048839, 25840971, 31844143)