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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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002670647Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Oct 6, 2021) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

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

Last Updated: Nov 10, 2024