NM_001754.5(RUNX1):c.367G>C (p.Asp123His) AND Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jul 29, 2019
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:: RCV000795718.5

Allele description [Variation Report for NM_001754.5(RUNX1):c.367G>C (p.Asp123His)]

NM_001754.5(RUNX1):c.367G>C (p.Asp123His)

Genes:

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

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.12

Genomic location:

Preferred name:

NM_001754.5(RUNX1):c.367G>C (p.Asp123His)

Other names:

NM_001754.4(RUNX1):c.367G>C

HGVS:

NC_000021.9:g.34880698C>G
NG_011402.2:g.1109014G>C
NM_001001890.3:c.286G>C
NM_001122607.2:c.286G>C
NM_001754.5:c.367G>CMANE SELECT
NP_001001890.1:p.Asp96His
NP_001116079.1:p.Asp96His
NP_001745.2:p.Asp123His
NP_001745.2:p.Asp123His
LRG_482t1:c.367G>C
LRG_482:g.1109014G>C
LRG_482p1:p.Asp123His
NC_000021.8:g.36252995C>G
NC_000021.8:g.36252995C>G
NM_001754.4:c.367G>C
p.Asp123His

Protein change:

D123H

Links:

dbSNP: rs373498347

NCBI 1000 Genomes Browser:

rs373498347

Molecular consequence:

NM_001001890.3:c.286G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001122607.2:c.286G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001754.5:c.367G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000935188	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 7, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18723428, 28933735, 28492532
SCV000965617	ClinGen Myeloid Malignancy Variant Curation Expert Panel	reviewed by expert panel (ClinGen MyeloMalig ACMG Specifications v1)	Uncertain significance (Jul 29, 2019)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000935188

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 7, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000965617

ClinGen Myeloid Malignancy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen MyeloMalig ACMG Specifications v1)

Uncertain significance
(Jul 29, 2019)

germline

curation

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

Citation Link

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, curation

Citations

PubMed

Clinical Outcomes and Co-Occurring Mutations in Patients with RUNX1-Mutated Acute Myeloid Leukemia.

Khan M, Cortes J, Kadia T, Naqvi K, Brandt M, Pierce S, Patel KP, Borthakur G, Ravandi F, Konopleva M, Kornblau S, Kantarjian H, Bhalla K, DiNardo CD.

Int J Mol Sci. 2017 Jul 26;18(8). doi:pii: E1618. 10.3390/ijms18081618.

PubMed [citation]

PMID:: 28933735
PMCID:: PMC5578010

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000935188.4

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 123 of the RUNX1 protein (p.Asp123His). This variant is present in population databases (rs373498347, gnomAD 0.003%). This missense change has been observed in individual(s) with acute myeloid leukemia and familial platelet disorder with propensity to myeloid malignancy (FPD/AML) (PMID: 18723428, 28933735). It has also been observed to segregate with disease in related individuals. This variant is also known as D96H. ClinVar contains an entry for this variant (Variation ID: 429813). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RUNX1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

From ClinGen Myeloid Malignancy Variant Curation Expert Panel, SCV000965617.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The NM_001754.4:c.367G>C (p.Asp123His) missense variant has a REVEL score >0.75 (0.943) (PP3). This variant affects one of the other residues (AA 105-204; not established as a hot spot by the MM-VCEP) within the RHD PM1_Supporting). The variant has been reported in one proband meeting at least one of the RUNX1-phenotypic criteria (PS4_Supporting; PMID: 18723428). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: PP3, PM1_Supporting, PS4_Supporting.

#	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: Feb 28, 2024

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