NM_000546.6(TP53):c.734G>C (p.Gly245Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 6, 2021
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:: RCV002379095.3

Allele description [Variation Report for NM_000546.6(TP53):c.734G>C (p.Gly245Ala)]

NM_000546.6(TP53):c.734G>C (p.Gly245Ala)

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.734G>C (p.Gly245Ala)

HGVS:

NC_000017.11:g.7674229C>G
NG_017013.2:g.18322G>C
NM_000546.6:c.734G>CMANE SELECT
NM_001126112.3:c.734G>C
NM_001126113.3:c.734G>C
NM_001126114.3:c.734G>C
NM_001126115.2:c.338G>C
NM_001126116.2:c.338G>C
NM_001126117.2:c.338G>C
NM_001126118.2:c.617G>C
NM_001276695.3:c.617G>C
NM_001276696.3:c.617G>C
NM_001276697.3:c.257G>C
NM_001276698.3:c.257G>C
NM_001276699.3:c.257G>C
NM_001276760.3:c.617G>C
NM_001276761.3:c.617G>C
NP_000537.3:p.Gly245Ala
NP_001119584.1:p.Gly245Ala
NP_001119585.1:p.Gly245Ala
NP_001119586.1:p.Gly245Ala
NP_001119587.1:p.Gly113Ala
NP_001119588.1:p.Gly113Ala
NP_001119589.1:p.Gly113Ala
NP_001119590.1:p.Gly206Ala
NP_001263624.1:p.Gly206Ala
NP_001263625.1:p.Gly206Ala
NP_001263626.1:p.Gly86Ala
NP_001263627.1:p.Gly86Ala
NP_001263628.1:p.Gly86Ala
NP_001263689.1:p.Gly206Ala
NP_001263690.1:p.Gly206Ala
LRG_321:g.18322G>C
NC_000017.10:g.7577547C>G
NM_000546.4:c.734G>C
P04637:p.Gly245Ala

Protein change:

G113A

Links:

UniProtKB: P04637#VAR_005971; dbSNP: rs121912656

NCBI 1000 Genomes Browser:

rs121912656

Molecular consequence:

NM_000546.6:c.734G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.734G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.734G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.734G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.338G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.338G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.338G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.617G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.617G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.617G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.257G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.257G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.257G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.617G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.617G>C - 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
SCV002670647	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 6, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12826609, 15541116, 20589832, 29979965, 30224644 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002670647

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 6, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Citations

PubMed

Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.

Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C.

Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9. Epub 2003 Jun 25.

PubMed [citation]

PMID:: 12826609
PMCID:: PMC166245

A modified yeast assay used on archival samples of localized prostate cancer tissue improves the detection of p53 abnormalities and increases their predictive value.

Shi XB, Gandour-Edwards R, Beckett LA, Deitch AD, de Vere White RW.

BJU Int. 2004 Nov;94(7):996-1002.

PubMed [citation]

PMID:: 15541116

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV002670647.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.G245A pathogenic mutation (also known as c.734G>C), located in coding exon 6 of the TP53 gene, results from a G to C substitution at nucleotide position 734. The glycine at codon 245 is replaced by alanine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Shi XB et al. BJU Int., 2004 Nov;94:996-1002). Additional functional studies conducted in human lung tumor cell lines showed this variant to have impaired G1 cell cycle arrest and DNA binding when compared to wild type (Perez Ret al., J. Cell. Physiol. 2010 Nov; 225(2):394-405). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Another alteration at the same codon, p.G245S (c.733G>A), has been reported in multiple individuals with clinical and family histories consistent with Li-Fraumeni syndrome (Toguchida J et al. N. Engl. J. Med. 1992 May;326:1301-8; Bougeard G et al. J Med Genet, 2001 Apr;38:253-7; Trkova M et al. Cancer Genet Cytogenet, 2003 Aug;145:60-4; Wong P et al. Gastroenterology. 2006 Jan;130:73-9; Ruijs MW et al. J Med Genet, 2010 Jun;47:421-8; Giacomazzi J et al. Cancer. 2013 Dec;119:4341-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: Jul 15, 2024

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