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NM_001754.5(RUNX1):c.166_196del (p.Leu56fs) AND Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Dec 9, 2023
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:
RCV001257572.2

Allele description [Variation Report for NM_001754.5(RUNX1):c.166_196del (p.Leu56fs)]

NM_001754.5(RUNX1):c.166_196del (p.Leu56fs)

Gene:
RUNX1:RUNX family transcription factor 1 [Gene - OMIM - HGNC]
Variant type:
Deletion
Cytogenetic location:
21q22.12
Genomic location:
Preferred name:
NM_001754.5(RUNX1):c.166_196del (p.Leu56fs)
Other names:
NM_001754.5(RUNX1):c.166_196del; p.Leu56fs
HGVS:
  • NC_000021.9:g.34886999_34887029del
  • NG_011402.2:g.1102684_1102714del
  • NM_001001890.3:c.85_115del
  • NM_001122607.2:c.85_115del
  • NM_001754.5:c.166_196delMANE SELECT
  • NP_001001890.1:p.Leu29fs
  • NP_001116079.1:p.Leu29fs
  • NP_001745.2:p.Leu56fs
  • LRG_482:g.1102684_1102714del
  • NC_000021.8:g.36259296_36259326del
  • NM_001754.5:c.166_196delTTGCCGCTGGGCGCCCCGGACGCCGGCGCTGMANE SELECT
Protein change:
L29fs
Links:
dbSNP: rs2058002908
NCBI 1000 Genomes Browser:
rs2058002908
Molecular consequence:
  • NM_001001890.3:c.85_115del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001122607.2:c.85_115del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001754.5:c.166_196del - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001432808Malcovati Lab, University of Pavia
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Sep 21, 2020) 		germlineresearch

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

SCV004176236ClinGen Myeloid Malignancy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen MyeloMalig ACMG Specifications v2)		Pathogenic
(Dec 9, 2023) 		germlinecuration

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedresearch, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Malcovati Lab, University of Pavia, SCV001432808.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen Myeloid Malignancy Variant Curation Expert Panel, SCV004176236.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_001754.5(RUNX1):c.166_196del (p.Leu56ProfsTer6) variant in RUNX1 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 4/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v2, v3, and v4 with at least 20x coverage (PM2_Supporting). It has been reported in a proband with thrombocytopenia and MDS/MPN-U and her "affected" sister (PMID: 37216690), as well as in 2 additional probands meeting phenotypic criteria for RUNX1 (PMID: 37406166) (PS4_Moderate, PP1 is not met). It has also been reported in a patient with MDS, but variant origin is unclear (cBioPortal.org - Papaemmanuil Lab, 2022). Furthermore, other pathogenic/likely pathogenic frameshift alterations in exon 4 have been reported (PMID: 35764482) (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PS4_Moderate, PM2_Supporting, and PM5_Supporting. (Version 2; date of approval)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 17, 2023