NM_000546.6(TP53):c.579T>A (p.His193Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 29, 2019
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:: RCV001024540.3

Allele description [Variation Report for NM_000546.6(TP53):c.579T>A (p.His193Gln)]

NM_000546.6(TP53):c.579T>A (p.His193Gln)

Gene:

TP53:tumor protein p53 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p13.1

Genomic location:

Preferred name:

NM_000546.6(TP53):c.579T>A (p.His193Gln)

HGVS:

NC_000017.11:g.7674952A>T
NG_017013.2:g.17599T>A
NM_000546.6:c.579T>AMANE SELECT
NM_001126112.3:c.579T>A
NM_001126113.3:c.579T>A
NM_001126114.3:c.579T>A
NM_001126115.2:c.183T>A
NM_001126116.2:c.183T>A
NM_001126117.2:c.183T>A
NM_001126118.2:c.462T>A
NM_001276695.3:c.462T>A
NM_001276696.3:c.462T>A
NM_001276697.3:c.102T>A
NM_001276698.3:c.102T>A
NM_001276699.3:c.102T>A
NM_001276760.3:c.462T>A
NM_001276761.3:c.462T>A
NP_000537.3:p.His193Gln
NP_001119584.1:p.His193Gln
NP_001119585.1:p.His193Gln
NP_001119586.1:p.His193Gln
NP_001119587.1:p.His61Gln
NP_001119588.1:p.His61Gln
NP_001119589.1:p.His61Gln
NP_001119590.1:p.His154Gln
NP_001263624.1:p.His154Gln
NP_001263625.1:p.His154Gln
NP_001263626.1:p.His34Gln
NP_001263627.1:p.His34Gln
NP_001263628.1:p.His34Gln
NP_001263689.1:p.His154Gln
NP_001263690.1:p.His154Gln
LRG_321:g.17599T>A
NC_000017.10:g.7578270A>T
NM_000546.4:c.579T>A

Protein change:

H154Q

Links:

dbSNP: rs1597368777

NCBI 1000 Genomes Browser:

rs1597368777

Molecular consequence:

NM_000546.6:c.579T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.579T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.579T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.579T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.183T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.183T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.183T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.462T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.462T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.462T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.102T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.102T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.102T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.462T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.462T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001186572	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jan 29, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001186572

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jan 29, 2019)

germline

clinical testing

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

Details of each submission

From Ambry Genetics, SCV001186572.4

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

Description

The p.H193Q variant (also known as c.579T>A), located in coding exon 5 of the TP53 gene, results from a T to A substitution at nucleotide position 579. The histidine at codon 193 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been identified as de novo in a patient meeting Chompret criteria (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have partial loss of transactivation capacity in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). This alteration has been reported as a somatic mutation 3 times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum. Mutat. 2007 Jun;28:622-9). Although this specific variant has not been reported in the literature as a germline alteration, two other alterations at this same codon (p.H193Y, p.H193R) have been reported as germline alterations in cases of Li Fraumeni syndrome (Petitjean A et al. IARC TP53 database [version R18, April 2016]. Hum Mutat. 2007 Jun;28(6):622-9; Frebourg T, Am. J. Hum. Genet. 1995 Mar; 56(3):608-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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: May 1, 2024

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