NM_001754.5(RUNX1):c.458del (p.Asn153fs) AND Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 6, 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:: RCV003630915.2

Allele description [Variation Report for NM_001754.5(RUNX1):c.458del (p.Asn153fs)]

NM_001754.5(RUNX1):c.458del (p.Asn153fs)

Genes:

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

Variant type:

Deletion

Cytogenetic location:

21q22.12

Genomic location:

Preferred name:

NM_001754.5(RUNX1):c.458del (p.Asn153fs)

HGVS:

NC_000021.9:g.34880608del
NG_011402.2:g.1109105del
NM_001001890.3:c.377del
NM_001122607.2:c.377del
NM_001754.5:c.458delMANE SELECT
NP_001001890.1:p.Asn126fs
NP_001116079.1:p.Asn126fs
NP_001745.2:p.Asn153Thrfs
NP_001745.2:p.Asn153fs
LRG_482t1:c.457del
LRG_482:g.1109105del
LRG_482p1:p.Asn153Thrfs
NC_000021.8:g.36252904del
NC_000021.8:g.36252905del
NM_001754.4:c.457delA

Protein change:

N126fs

Molecular consequence:

NM_001001890.3:c.377del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001122607.2:c.377del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001754.5:c.458del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV004452200	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18723428, 24100448, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004452200

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 6, 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

Five new pedigrees with inherited RUNX1 mutations causing familial platelet disorder with propensity to myeloid malignancy.

Owen CJ, Toze CL, Koochin A, Forrest DL, Smith CA, Stevens JM, Jackson SC, Poon MC, Sinclair GD, Leber B, Johnson PR, Macheta A, Yin JA, Barnett MJ, Lister TA, Fitzgibbon J.

Blood. 2008 Dec 1;112(12):4639-45. doi: 10.1182/blood-2008-05-156745. Epub 2008 Aug 21.

PubMed [citation]

PMID:: 18723428

Enrichment of FLI1 and RUNX1 mutations in families with excessive bleeding and platelet dense granule secretion defects.

Stockley J, Morgan NV, Bem D, Lowe GC, Lordkipanidzé M, Dawood B, Simpson MA, Macfarlane K, Horner K, Leo VC, Talks K, Motwani J, Wilde JT, Collins PW, Makris M, Watson SP, Daly ME; UK Genotyping and Phenotyping of Platelets Study Group..

Blood. 2013 Dec 12;122(25):4090-3. doi: 10.1182/blood-2013-06-506873. Epub 2013 Oct 7.

PubMed [citation]

PMID:: 24100448
PMCID:: PMC3862284

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004452200.1

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

Description

This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn153Thrfs*23) in the RUNX1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RUNX1 are known to be pathogenic (PMID: 18723428, 24100448).

#	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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