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NM_001754.5(RUNX1):c.489dup (p.Val164fs) AND Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 13, 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:
RCV003408207.1

Allele description [Variation Report for NM_001754.5(RUNX1):c.489dup (p.Val164fs)]

NM_001754.5(RUNX1):c.489dup (p.Val164fs)

Genes:
RUNX1:RUNX family transcription factor 1 [Gene - OMIM - HGNC]
RUNX1-AS1:RUNX1 antisense RNA 1 [Gene - HGNC]
Variant type:
Duplication
Cytogenetic location:
21q22.12
Genomic location:
Preferred name:
NM_001754.5(RUNX1):c.489dup (p.Val164fs)
Other names:
NM_001754.5(RUNX1):c.489dup; p.Val164fs
HGVS:
  • NC_000021.9:g.34880578dup
  • NG_011402.2:g.1109136dup
  • NM_001001890.3:c.408dup
  • NM_001122607.2:c.408dup
  • NM_001754.5:c.489dupMANE SELECT
  • NP_001001890.1:p.Val137fs
  • NP_001116079.1:p.Val137fs
  • NP_001745.2:p.Val164Cysfs
  • NP_001745.2:p.Val164fs
  • LRG_482t1:c.487dup
  • LRG_482:g.1109136dup
  • LRG_482p1:p.Val164Cysfs
  • NC_000021.8:g.36252875dup
  • NM_001754.4:c.487dup
  • NM_001754.4:c.489dup
Protein change:
V137fs
Molecular consequence:
  • NM_001001890.3:c.408dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001122607.2:c.408dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001754.5:c.489dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Identifiers:
MONDO: MONDO:0011071; MedGen: CN281654

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004123215ClinGen Myeloid Malignancy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen MyeloMalig ACMG Specifications v2)		Pathogenic
(Nov 13, 2023) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen Myeloid Malignancy Variant Curation Expert Panel, SCV004123215.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.489dup (p.Val164Cysfs*49) variant in RUNX1 is a frameshift duplication predicted to cause a premature stop codon in biologically-relevant exon 7/9 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The variant is absent from gnomAD v2 and v3 with a mean coverage of at least 20X (PM2_Supporting). It has also been described in a 67yo male with AML who had a daughter with AML at age 21 (HSCT at age 26), and an additional daughter and 2 sons with thrombocytopenia, but germline origin was not confirmed (PMID: 32804409, cited by PMID: 35884491) (PS4_Supporting does not apply). Regardless, there are 25 nonsense/frameshift variants classified as pathogenic by the MM-VCEP in exons 3-7 (two per exon) with sufficient molecular and specific clinical data (PMID: 35764482) (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PVS1, PM2_Supporting, and PM5_Supporting.

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

Last Updated: Oct 8, 2024