NM_001754.5(RUNX1):c.467C>A (p.Ala156Glu) AND Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jul 30, 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:: RCV000015558.27

Allele description [Variation Report for NM_001754.5(RUNX1):c.467C>A (p.Ala156Glu)]

NM_001754.5(RUNX1):c.467C>A (p.Ala156Glu)

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.467C>A (p.Ala156Glu)

Other names:

NM_001754.4(RUNX1):c.467C>A

HGVS:

NC_000021.9:g.34880598G>T
NG_011402.2:g.1109114C>A
NM_001001890.3:c.386C>A
NM_001122607.2:c.386C>A
NM_001754.5:c.467C>AMANE SELECT
NP_001001890.1:p.Ala129Glu
NP_001116079.1:p.Ala129Glu
NP_001745.2:p.Ala156Glu
LRG_482:g.1109114C>A
NC_000021.8:g.36252895G>T
p.Ala156Glu

Protein change:

A129E; ALA129GLU

Links:

OMIM: 151385.0010; dbSNP: rs267607026

NCBI 1000 Genomes Browser:

rs267607026

Molecular consequence:

NM_001001890.3:c.386C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001122607.2:c.386C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001754.5:c.467C>A - 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
SCV000035823	OMIM	no assertion criteria provided	Pathogenic (May 28, 2009)	unknown	literature only	PubMed (1) [See all records that cite this PMID]
SCV000965619	ClinGen Myeloid Malignancy Variant Curation Expert Panel	reviewed by expert panel (ClinGen MyeloMalig ACMG Specifications v1)	Likely pathogenic (Jul 30, 2019)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 27112265, 19357396 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000035823

OMIM

no assertion criteria provided

Pathogenic
(May 28, 2009)

unknown

literature only

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

SCV000965619

ClinGen Myeloid Malignancy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen MyeloMalig ACMG Specifications v1)

Likely pathogenic
(Jul 30, 2019)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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	curation
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Haematological spectrum and genotype-phenotype correlations in nine unrelated families with RUNX1 mutations from the French network on inherited platelet disorders.

Latger-Cannard V, Philippe C, Bouquet A, Baccini V, Alessi MC, Ankri A, Bauters A, Bayart S, Cornillet-Lefebvre P, Daliphard S, Mozziconacci MJ, Renneville A, Ballerini P, Leverger G, Sobol H, Jonveaux P, Preudhomme C, Nurden P, Lecompte T, Favier R.

Orphanet J Rare Dis. 2016 Apr 26;11:49. doi: 10.1186/s13023-016-0432-0.

PubMed [citation]

PMID:: 27112265
PMCID:: PMC4845427

High frequency of RUNX1 biallelic alteration in acute myeloid leukemia secondary to familial platelet disorder.

Preudhomme C, Renneville A, Bourdon V, Philippe N, Roche-Lestienne C, Boissel N, Dhedin N, André JM, Cornillet-Lefebvre P, Baruchel A, Mozziconacci MJ, Sobol H.

Blood. 2009 May 28;113(22):5583-7. doi: 10.1182/blood-2008-07-168260. Epub 2009 Apr 8.

PubMed [citation]

PMID:: 19357396

Details of each submission

From OMIM, SCV000035823.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 7 members of a family with familial platelet disorder (FPDMM; 601399), Preudhomme et al. (2009) identified a heterozygous 386C-A transversion in the RUNX1 gene, resulting in an ala129-to-glu (A129E) substitution. Five of the 7 developed fatal acute myeloid leukemia. All 3 patients analyzed who developed AML were found to carry a second somatic mutation in the RUNX1 gene: a frameshift, an arg135-to-ser (R135S) substitution, and an acquired trisomy 21 associated with duplication of the mutated allele, respectively.

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

From ClinGen Myeloid Malignancy Variant Curation Expert Panel, SCV000965619.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

The NM_001754.4:c.467C>A (p.Ala156Glu) variant was found to co-segregate with disease in multiple affected family members, with seven meioses observed in one family (PP1_Strong; PMID: 19357396, 27112265). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It affects one of the residues (AA 105-204) within the RHD (PM1_Supporting). This missense variant has a REVEL score >0.75 (0.906) (PP3). It has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_ Supporting; PMID: 19357396, 27112265). In summary, this variant meets criteria to be classified as likely pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP1_Strong, PM2, PP3, PM1_Supporting, PS4_Supporting.

#	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 14, 2023

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