NM_001754.5(RUNX1):c.193G>A (p.Ala65Thr) AND Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 25, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003630183.2

Allele description [Variation Report for NM_001754.5(RUNX1):c.193G>A (p.Ala65Thr)]

NM_001754.5(RUNX1):c.193G>A (p.Ala65Thr)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.12

Genomic location:

Preferred name:

NM_001754.5(RUNX1):c.193G>A (p.Ala65Thr)

Other names:

NM_001754.5(RUNX1):c.193G>A; p.Ala65Thr

HGVS:

NC_000021.9:g.34887001C>T
NG_011402.2:g.1102711G>A
NG_144242.1:g.476C>T
NM_001001890.3:c.112G>A
NM_001122607.2:c.112G>A
NM_001754.5:c.193G>AMANE SELECT
NP_001001890.1:p.Ala38Thr
NP_001116079.1:p.Ala38Thr
NP_001745.2:p.Ala65Thr
NP_001745.2:p.Ala65Thr
LRG_482t1:c.193G>A
LRG_482:g.1102711G>A
LRG_482p1:p.Ala65Thr
NC_000021.8:g.36259298C>T
NM_001754.4:c.193G>A

Protein change:

A38T

Molecular consequence:

NM_001001890.3:c.112G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001122607.2:c.112G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001754.5:c.193G>A - 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

Recent activity

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Homo sapiens steroid 5 alpha-reductase 2-like (SRD5A2L), mRNA
Homo sapiens steroid 5 alpha-reductase 2-like (SRD5A2L), mRNA
gi|13375784|ref|NM_024592.1|

Nucleotide
cardiac muscle myosin heavy chain 6 alpha, partial [Blennius multifilis]
cardiac muscle myosin heavy chain 6 alpha, partial [Blennius multifilis]
gi|2553036293|gb|WKW49204.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004400849	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 25, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004400849

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 25, 2023)

germline

clinical testing

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

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

Citations

PubMed

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004400849.1

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

Description

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. 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. This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 65 of the RUNX1 protein (p.Ala65Thr).

#	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: Nov 3, 2024

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