NM_001754.4(RUNX1):c.958C>T (p.Arg320Ter) AND Familial platelet disorder with associated myeloid malignancy

Clinical significance:Pathogenic (Last evaluated: Jan 14, 2020)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001078218.2

Allele description [Variation Report for NM_001754.4(RUNX1):c.958C>T (p.Arg320Ter)]

NM_001754.4(RUNX1):c.958C>T (p.Arg320Ter)

Gene:
RUNX1:RUNX family transcription factor 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
21q22.12
Genomic location:
Preferred name:
NM_001754.4(RUNX1):c.958C>T (p.Arg320Ter)
HGVS:
  • NC_000021.9:g.34799310G>A
  • NG_011402.2:g.1190402C>T
  • NM_001001890.3:c.877C>T
  • NM_001754.4:c.958C>T
  • NP_001001890.1:p.Arg293Ter
  • NP_001745.2:p.Arg320Ter
  • LRG_482t1:c.958C>T
  • LRG_482:g.1190402C>T
  • LRG_482p1:p.Arg320Ter
  • NC_000021.8:g.36171607G>A
  • NM_001754.4(RUNX1):c.958C>T
  • p.Arg320*
  • p.Arg320Ter
Protein change:
R293*
Links:
dbSNP: rs1569008655
NCBI 1000 Genomes Browser:
rs1569008655
Molecular consequence:
  • NM_001001890.3:c.877C>T - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001754.4:c.958C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Familial platelet disorder with associated myeloid malignancy (FPDMM)
Synonyms:
Platelet disorder, Aspirin-like; Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1; Familial Platelet Disorder with Propensity to Acute Myelogenous Leukemia; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0100083; MedGen: C1832388; Orphanet: 71290; OMIM: 601399

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001244327ClinGen Myeloid Malignancy Variant Curation Expert Panelreviewed by expert panel
Pathogenic
(Jan 14, 2020)
germlinecuration

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001575462Invitaecriteria provided, single submitter
Likely pathogenic
(Jun 26, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Functional features of RUNX1 mutants in acute transformation of chronic myeloid leukemia and their contribution to inducing murine full-blown leukemia.

Zhao LJ, Wang YY, Li G, Ma LY, Xiong SM, Weng XQ, Zhang WN, Wu B, Chen Z, Chen SJ.

Blood. 2012 Mar 22;119(12):2873-82. doi: 10.1182/blood-2011-08-370981. Epub 2012 Feb 7.

PubMed [citation]
PMID:
22318203

A ZMYM2-FGFR1 8p11 myeloproliferative neoplasm with a novel nonsense RUNX1 mutation and tumor lysis upon imatinib treatment.

Buijs A, van Wijnen M, van den Blink D, van Gijn M, Klein SK.

Cancer Genet. 2013 Apr;206(4):140-4. doi: 10.1016/j.cancergen.2013.04.001.

PubMed [citation]
PMID:
23751892
See all PubMed Citations (7)

Details of each submission

From ClinGen Myeloid Malignancy Variant Curation Expert Panel, SCV001244327.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (4)

Description

The NM_001754.4:c.958C>T (p.Arg320Ter) variant is a nonsense variant that is not expected to result in nonsense-mediated mRNA decay, but the predicted truncated/altered region (removes aa 320 - 480) is critical to protein function (PVS1_Strong). This variant was found to co-segregate with disease in multiple affected family members, with more than seven (14) meioses observed across 2 families (PP1_Strong; from internal laboratory data). The variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2). It has been reported in two probands meeting at least one of the RUNX1-phenotypic criteria (PS4_Moderate; from internal laboratory data). 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_Strong, PP1_Strong, PM2, PS4_Moderate.

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

From Invitae, SCV001575462.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change results in a premature translational stop signal in the RUNX1 gene (p.Arg320*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 161 amino acids of the RUNX1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of familial platelet disorder with associated myeloid malignancies (PMID: 18723428, 31064749, 25840971, external communications). It has also been observed to segregate with disease in related individuals. This variant is also known in the literature as c.877C>T (R292*). ClinVar contains an entry for this variant (Variation ID: 618862). This variant has been reported to affect RUNX1 protein function (PMID: 25840971). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Sep 23, 2021

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