NM_001754.5(RUNX1):c.318G>T (p.Trp106Cys) AND Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 11, 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:: RCV003630792.2

Allele description [Variation Report for NM_001754.5(RUNX1):c.318G>T (p.Trp106Cys)]

NM_001754.5(RUNX1):c.318G>T (p.Trp106Cys)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.12

Genomic location:

Preferred name:

NM_001754.5(RUNX1):c.318G>T (p.Trp106Cys)

HGVS:

NC_000021.9:g.34886876C>A
NG_011402.2:g.1102836G>T
NG_144242.1:g.351C>A
NM_001001890.3:c.237G>T
NM_001122607.2:c.237G>T
NM_001754.5:c.318G>TMANE SELECT
NP_001001890.1:p.Trp79Cys
NP_001116079.1:p.Trp79Cys
NP_001745.2:p.Trp106Cys
NP_001745.2:p.Trp106Cys
LRG_482t1:c.318G>T
LRG_482:g.1102836G>T
LRG_482p1:p.Trp106Cys
NC_000021.8:g.36259173C>A
NM_001754.4:c.318G>T

Protein change:

W106C

Molecular consequence:

NM_001001890.3:c.237G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001122607.2:c.237G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001754.5:c.318G>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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Homo sapiens pejvakin (PJVK), transcript variant 6, mRNA
Homo sapiens pejvakin (PJVK), transcript variant 6, mRNA
gi|1624525640|ref|NM_001369912.1|

Nucleotide
PTGES [Pelodiscus sinensis]
PTGES [Pelodiscus sinensis]
Gene ID:102449946

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004500863	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 11, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22012064, 23817177, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004500863

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 11, 2023)

germline

clinical testing

PubMed (3)
[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

The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations.

Huang G, Zhao X, Wang L, Elf S, Xu H, Zhao X, Sashida G, Zhang Y, Liu Y, Lee J, Menendez S, Yang Y, Yan X, Zhang P, Tenen DG, Osato M, Hsieh JJ, Nimer SD.

Blood. 2011 Dec 15;118(25):6544-52. doi: 10.1182/blood-2010-11-317909. Epub 2011 Oct 19.

PubMed [citation]

PMID:: 22012064
PMCID:: PMC3242717

RUNX1 meets MLL: epigenetic regulation of hematopoiesis by two leukemia genes.

Koh CP, Wang CQ, Ng CE, Ito Y, Araki M, Tergaonkar V, Huang G, Osato M.

Leukemia. 2013 Sep;27(9):1793-802. doi: 10.1038/leu.2013.200. Epub 2013 Jul 2. Review.

PubMed [citation]

PMID:: 23817177

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004500863.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

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 are conflicting or provide insufficient evidence to determine the effect of this variant on RUNX1 function (PMID: 22012064, 23817177). 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. This variant is also known as W79C. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 106 of the RUNX1 protein (p.Trp106Cys).

#	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: Sep 29, 2024

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