NM_001754.5(RUNX1):c.422C>T (p.Ser141Leu) AND Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 7, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000804289.7

Allele description [Variation Report for NM_001754.5(RUNX1):c.422C>T (p.Ser141Leu)]

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

Genes:

RUNX1:RUNX family transcription factor 1 [Gene - OMIM - HGNC]
RUNX1-AS1:RUNX1 antisense RNA 1 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.12

Genomic location:

Preferred name:

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

Other names:

NM_001754.5(RUNX1):c.422C>T; p.Ser141Leu

HGVS:

NC_000021.9:g.34880643G>A
NG_011402.2:g.1109069C>T
NM_001001890.3:c.341C>T
NM_001122607.2:c.341C>T
NM_001754.5:c.422C>TMANE SELECT
NP_001001890.1:p.Ser114Leu
NP_001116079.1:p.Ser114Leu
NP_001745.2:p.Ser141Leu
NP_001745.2:p.Ser141Leu
LRG_482t1:c.422C>T
LRG_482:g.1109069C>T
LRG_482p1:p.Ser141Leu
NC_000021.8:g.36252940G>A
NM_001754.4:c.422C>T

Protein change:

S114L

Links:

dbSNP: rs1601516118

NCBI 1000 Genomes Browser:

rs1601516118

Molecular consequence:

NM_001001890.3:c.341C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001122607.2:c.341C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001754.5:c.422C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1
Synonyms:: Platelet disorder, Aspirin-like; Familial platelet disorder with associated myeloid malignancy; Familial Platelet Disorder with Propensity to Acute Myelogenous Leukemia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0100083; MeSH: C563324; MedGen: C1832388; Orphanet: 71290; OMIM: 601399

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000944192	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 7, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31048839, 25840971, 34028844, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000944192

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 7, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Thermodynamic investigation of DNA-binding affinity of wild-type and mutant transcription factor RUNX1.

Wu F, Song T, Yao Y, Song Y.

PLoS One. 2019;14(5):e0216203. doi: 10.1371/journal.pone.0216203.

PubMed [citation]

PMID:: 31048839
PMCID:: PMC6497270

Biological Activities of RUNX1 Mutants Predict Secondary Acute Leukemia Transformation from Chronic Myelomonocytic Leukemia and Myelodysplastic Syndromes.

Tsai SC, Shih LY, Liang ST, Huang YJ, Kuo MC, Huang CF, Shih YS, Lin TH, Chiu MC, Liang DC.

Clin Cancer Res. 2015 Aug 1;21(15):3541-51. doi: 10.1158/1078-0432.CCR-14-2203. Epub 2015 Apr 3.

PubMed [citation]

PMID:: 25840971

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000944192.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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. ClinVar contains an entry for this variant (Variation ID: 649370). 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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