NM_001754.5(RUNX1):c.259G>T (p.Gly87Cys) AND Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jul 26, 2019
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000527760.11

Allele description [Variation Report for NM_001754.5(RUNX1):c.259G>T (p.Gly87Cys)]

NM_001754.5(RUNX1):c.259G>T (p.Gly87Cys)

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.259G>T (p.Gly87Cys)

Other names:

NM_001754.4(RUNX1):c.259G>T

HGVS:

NC_000021.9:g.34886935C>A
NG_011402.2:g.1102777G>T
NM_001001890.3:c.178G>T
NM_001122607.2:c.178G>T
NM_001754.5:c.259G>TMANE SELECT
NP_001001890.1:p.Gly60Cys
NP_001116079.1:p.Gly60Cys
NP_001745.2:p.Gly87Cys
NP_001745.2:p.Gly87Cys
LRG_482t1:c.259G>T
LRG_482:g.1102777G>T
LRG_482p1:p.Gly87Cys
NC_000021.8:g.36259232C>A
NM_001754.4:c.259G>T
p.Gly87Cys

Protein change:

G60C

Links:

dbSNP: rs561166961

NCBI 1000 Genomes Browser:

rs561166961

Molecular consequence:

NM_001001890.3:c.178G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001122607.2:c.178G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001754.5:c.259G>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
SCV000638138	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 28, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31309983, 32051554, 33692461, 28492532
SCV000965650	ClinGen Myeloid Malignancy Variant Curation Expert Panel	reviewed by expert panel (ClinGen MyeloMalig ACMG Specifications v1)	Uncertain significance (Jul 26, 2019)	germline	curation	Citation Link,
SCV004807431	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 26, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000638138

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 28, 2023)

germline

clinical testing

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

SCV000965650

ClinGen Myeloid Malignancy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen MyeloMalig ACMG Specifications v1)

Uncertain significance
(Jul 26, 2019)

germline

curation

Citation Link,

SCV004807431

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 26, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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, curation

Citations

PubMed

Germline Predisposition to Hematolymphoid Neoplasia.

Weinberg OK, Kuo F, Calvo KR.

Am J Clin Pathol. 2019 Aug 1;152(3):258-276. doi: 10.1093/ajcp/aqz067. Review.

PubMed [citation]

PMID:: 31309983
PMCID:: PMC7179513

Genetic basis for iMCD-TAFRO.

Yoshimi A, Trippett TM, Zhang N, Chen X, Penson AV, Arcila ME, Pichardo J, Baik J, Sigler A, Harada H, Fajgenbaum DC, Dogan A, Abdel-Wahab O, Xiao W.

Oncogene. 2020 Apr;39(15):3218-3225. doi: 10.1038/s41388-020-1204-9. Epub 2020 Feb 12.

PubMed [citation]

PMID:: 32051554
PMCID:: PMC7148173

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000638138.6

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 87 of the RUNX1 protein (p.Gly87Cys). This variant is present in population databases (rs561166961, gnomAD 0.003%). This missense change has been observed in individual(s) with iMCD-TAFRO syndrome (PMID: 31309983, 32051554). This variant is also known as p.Gly60Cys. ClinVar contains an entry for this variant (Variation ID: 436618). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RUNX1 function (PMID: 32051554, 33692461). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.

#	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

From ClinGen Myeloid Malignancy Variant Curation Expert Panel, SCV000965650.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_001754.4:c.259G>T (p.Gly87Cys) variant is a missense variant has a REVEL score >0.75 (0.918) (PP3). AMR Subpopulation of 1000 Genomes Allele frequency 0.00144 with 1 allele out of 694 alleles. In summary, the clinical significance of this variant is uncertain (VUS). ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3.

#	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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004807431.1

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

#	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 13, 2024

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