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NM_001754.5(RUNX1):c.166_193dup (p.Ala65fs) AND Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 26, 2024
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:
RCV001376068.2

Allele description [Variation Report for NM_001754.5(RUNX1):c.166_193dup (p.Ala65fs)]

NM_001754.5(RUNX1):c.166_193dup (p.Ala65fs)

Gene:
RUNX1:RUNX family transcription factor 1 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
21q22.12
Genomic location:
Preferred name:
NM_001754.5(RUNX1):c.166_193dup (p.Ala65fs)
Other names:
NM_001754.5(RUNX1):c.166_193dup; p.Ala65fs
HGVS:
  • NC_000021.9:g.34887005_34887032dup
  • NG_011402.2:g.1102684_1102711dup
  • NM_001001890.3:c.85_112dup
  • NM_001122607.2:c.85_112dup
  • NM_001754.5:c.166_193dupMANE SELECT
  • NP_001001890.1:p.Ala38fs
  • NP_001116079.1:p.Ala38fs
  • NP_001745.2:p.Ala65fs
  • NP_001745.2:p.Ala65fs
  • LRG_482t1:c.166_193dup
  • LRG_482:g.1102684_1102711dup
  • LRG_482p1:p.Ala65fs
  • NC_000021.8:g.36259297_36259298insCGCCGGCGTCCGGGGCGCCCAGCGGCAA
  • NC_000021.8:g.36259302_36259329dup
  • NM_001754.4:c.166_193dup
Protein change:
A38fs
Links:
dbSNP: rs1569084530
NCBI 1000 Genomes Browser:
rs1569084530
Molecular consequence:
  • NM_001001890.3:c.85_112dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001122607.2:c.85_112dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001754.5:c.166_193dup - 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
SCV001573091ClinGen Myeloid Malignancy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen MyeloMalig ACMG Specifications v2)		Pathogenic
(Mar 26, 2024) 		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, SCV001573091.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.166_193dup (p.Ala65Valfs*82) variant is a 28-bp duplication causing a frameshift that is predicted to introduce a premature stop codon and expected to result in nonsense-mediated mRNA decay (PVS1). This variant is completely absent from all population databases (gnomAD v2.1.1 and v3) with at least 20x coverage for RUNX1 (PM2_supporting). This variant is a nonsense/frameshift variants that is downstream of c.98 (PM5_Supporting). The variant has not been reported in FPD/AML patients in the literature to the best of our knowledge; however one patient meeting RUNX1-phenotype criteria is reported from a clinical laboratory (PS4_Supporting; SCV000820350.2). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PVS1, PM2_supporting, PS4_Supporting, PM5_supporting.

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

Last Updated: Sep 29, 2024