NM_000546.5(TP53):c.836G>A (p.Gly279Glu) AND Hereditary cancer-predisposing syndrome

Clinical significance:Likely pathogenic (Last evaluated: Feb 21, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000492354.2

Allele description [Variation Report for NM_000546.5(TP53):c.836G>A (p.Gly279Glu)]

NM_000546.5(TP53):c.836G>A (p.Gly279Glu)

Gene:
TP53:tumor protein p53 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000546.5(TP53):c.836G>A (p.Gly279Glu)
HGVS:
  • NC_000017.11:g.7673784C>T
  • NG_017013.2:g.18767G>A
  • NM_000546.5:c.836G>A
  • NM_001126112.2:c.836G>A
  • NM_001126113.2:c.836G>A
  • NM_001126114.2:c.836G>A
  • NM_001126115.1:c.440G>A
  • NM_001126116.1:c.440G>A
  • NM_001126117.1:c.440G>A
  • NM_001126118.1:c.719G>A
  • NM_001276695.2:c.719G>A
  • NM_001276696.2:c.719G>A
  • NM_001276697.2:c.359G>A
  • NM_001276698.2:c.359G>A
  • NM_001276699.2:c.359G>A
  • NM_001276760.2:c.719G>A
  • NM_001276761.2:c.719G>A
  • NP_000537.3:p.Gly279Glu
  • NP_001119584.1:p.Gly279Glu
  • NP_001119585.1:p.Gly279Glu
  • NP_001119586.1:p.Gly279Glu
  • NP_001119587.1:p.Gly147Glu
  • NP_001119588.1:p.Gly147Glu
  • NP_001119589.1:p.Gly147Glu
  • NP_001119590.1:p.Gly240Glu
  • NP_001263624.1:p.Gly240Glu
  • NP_001263625.1:p.Gly240Glu
  • NP_001263626.1:p.Gly120Glu
  • NP_001263627.1:p.Gly120Glu
  • NP_001263628.1:p.Gly120Glu
  • NP_001263689.1:p.Gly240Glu
  • NP_001263690.1:p.Gly240Glu
  • LRG_321t1:c.836G>A
  • LRG_321t2:c.836G>A
  • LRG_321t3:c.836G>A
  • LRG_321t4:c.836G>A
  • LRG_321t5:c.440G>A
  • LRG_321t6:c.440G>A
  • LRG_321t7:c.440G>A
  • LRG_321t8:c.719G>A
  • LRG_321:g.18767G>A
  • LRG_321:p.Gly279Glu
  • LRG_321p1:p.Gly279Glu
  • LRG_321p3:p.Gly279Glu
  • LRG_321p4:p.Gly279Glu
  • LRG_321p5:p.Gly147Glu
  • LRG_321p6:p.Gly147Glu
  • LRG_321p7:p.Gly147Glu
  • LRG_321p8:p.Gly240Glu
  • NC_000017.10:g.7577102C>T
  • NM_000546.4:c.836G>A
Protein change:
G120E
Links:
dbSNP: rs1064793881
NCBI 1000 Genomes Browser:
rs1064793881
Molecular consequence:
  • NM_000546.5:c.836G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.2:c.836G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.2:c.836G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.2:c.836G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.1:c.440G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.1:c.440G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.1:c.440G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.1:c.719G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.2:c.719G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.2:c.719G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.2:c.359G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.2:c.359G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.2:c.359G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.2:c.719G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.2:c.719G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000581126Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Feb 21, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

p53 mutants exhibiting enhanced transcriptional activation and altered promoter selectivity are revealed using a sensitive, yeast-based functional assay.

Inga A, Monti P, Fronza G, Darden T, Resnick MA.

Oncogene. 2001 Jan 25;20(4):501-13.

PubMed [citation]
PMID:
11313981

The biological impact of the human master regulator p53 can be altered by mutations that change the spectrum and expression of its target genes.

Menendez D, Inga A, Resnick MA.

Mol Cell Biol. 2006 Mar;26(6):2297-308.

PubMed [citation]
PMID:
16508005
PMCID:
PMC1430278
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000581126.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)

Description

The p.G279E variant (also known as c.836G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 836. The glycine at codon 279 is replaced by glutamic acid, an amino acid with a few similar properties. <span style="background-color:initial">Per the IARC TP53 Database, this alteration has been reported as a somatic alteration 53 times, however this has not been reported as a germline alteration in any Li-Fraumeni syndrome families (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum Mutat. 2007 Jun;28(6):622-9). <span style="background-color:initial">This alteration is located in the functionally critical DNA-binding domain. A number of functional assays in both yeast and mammalian cells have shown this alteration to be devoid of transactivation activity, deficient in the induction of apoptosis, and unable to suppress cell growth after UV irradiation (Kato S et al.Proc Natl Acad Sci USA<span style="background-color:initial">. 2003 Jul 8;100(14):8424-9; Menendez D, Mol. Cell. Biol.<span style="background-color:initial"> 2006 Mar; 26(6):2297-308; <span style="background-color:initial">Inga A, Oncogene 2001 Jan; 20(4):501-13; <span style="background-color:initial">Rokudai Set al. J Biol Chem. 2009 Jan 2;284(1):237-44). <span style="background-color:initial">Additionally, this variant has been shown to exhibit strong dominant negative characteristics (<span style="background-color:initial">Dearth LR, Carcinogenesis 2007 Feb; 28(2):289-98; <span style="background-color:initial">Brachmann RK, Proc. Natl. Acad. Sci. U.S.A. 1996 Apr; 93(9):4091-5<span style="background-color:initial">). Structural analysis indicates that G279 is adjacent to several DNA binding residues, and the p.G279E change creates severe structural perturbations (>15 kcal/mol) resulting in a destabilization of the proper folding of the adjacent loop (internal analysis). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8). <span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico <span style="background-color:initial">analysis. <span style="background-color:initial">Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Jul 10, 2021

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