NM_000546.6(TP53):c.797G>A (p.Gly266Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 21, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000492556.9

Allele description [Variation Report for NM_000546.6(TP53):c.797G>A (p.Gly266Glu)]

NM_000546.6(TP53):c.797G>A (p.Gly266Glu)

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.797G>A (p.Gly266Glu)

HGVS:

NC_000017.11:g.7673823C>T
NG_017013.2:g.18728G>A
NM_000546.6:c.797G>AMANE SELECT
NM_001126112.3:c.797G>A
NM_001126113.3:c.797G>A
NM_001126114.3:c.797G>A
NM_001126115.2:c.401G>A
NM_001126116.2:c.401G>A
NM_001126117.2:c.401G>A
NM_001126118.2:c.680G>A
NM_001276695.3:c.680G>A
NM_001276696.3:c.680G>A
NM_001276697.3:c.320G>A
NM_001276698.3:c.320G>A
NM_001276699.3:c.320G>A
NM_001276760.3:c.680G>A
NM_001276761.3:c.680G>A
NP_000537.3:p.Gly266Glu
NP_000537.3:p.Gly266Glu
NP_001119584.1:p.Gly266Glu
NP_001119585.1:p.Gly266Glu
NP_001119586.1:p.Gly266Glu
NP_001119587.1:p.Gly134Glu
NP_001119587.1:p.Gly134Glu
NP_001119588.1:p.Gly134Glu
NP_001119589.1:p.Gly134Glu
NP_001119590.1:p.Gly227Glu
NP_001263624.1:p.Gly227Glu
NP_001263625.1:p.Gly227Glu
NP_001263626.1:p.Gly107Glu
NP_001263627.1:p.Gly107Glu
NP_001263628.1:p.Gly107Glu
NP_001263689.1:p.Gly227Glu
NP_001263690.1:p.Gly227Glu
LRG_321t1:c.797G>A
LRG_321t5:c.401G>A
LRG_321:g.18728G>A
LRG_321p1:p.Gly266Glu
LRG_321p5:p.Gly134Glu
NC_000017.10:g.7577141C>T
NM_000546.4:c.797G>A
NM_000546.5:c.797G>A
NM_001126115.1:c.401G>A

Protein change:

G107E

Links:

dbSNP: rs193920774

NCBI 1000 Genomes Browser:

rs193920774

Molecular consequence:

NM_000546.6:c.797G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.797G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.797G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.797G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.401G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.401G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.401G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.320G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.320G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.320G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.680G>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
SCV000581084	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 21, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11429705, 12917626, 20505364, 22198284, 24651015 Citation Link,
SCV002582355	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 18, 2022)	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

SCV000581084

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 21, 2023)

germline

clinical testing

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

Citation Link,

SCV002582355

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 18, 2022)

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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

p53 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements.

Campomenosi P, Monti P, Aprile A, Abbondandolo A, Frebourg T, Gold B, Crook T, Inga A, Resnick MA, Iggo R, Fronza G.

Oncogene. 2001 Jun 14;20(27):3573-9.

PubMed [citation]

PMID:: 11429705

Characterization of the p53 mutants ability to inhibit p73 beta transactivation using a yeast-based functional assay.

Monti P, Campomenosi P, Ciribilli Y, Iannone R, Aprile A, Inga A, Tada M, Menichini P, Abbondandolo A, Fronza G.

Oncogene. 2003 Aug 14;22(34):5252-60.

PubMed [citation]

PMID:: 12917626

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000581084.6

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

Description

The p.G266E pathogenic mutation (also known as c.797G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 797. The glycine at codon 266 is replaced by glutamic acid, an amino acid with similar properties. This variant has been identified as a somatic mutation in tumors 91 times, and as a germline alteration in one individual with medulloblastoma (Petitjean A et al. IARC TP53 database [version R18, April 2016]. Hum. Mutat. 2007 Jun;28(6):622-9; Kool M et al. Cancer Cell. 2014 Mar; 25(3):393-405). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based functional studies (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. U.S.A. 2003 Jul 8;100(14):8424-9; Campomenosi P et al. Oncogene. 2001 Jun; 20(27):3573-9). 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; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science 1994 Jul;265(5170):346-55). 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

From Genome-Nilou Lab, SCV002582355.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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