NM_000546.6(TP53):c.797G>T (p.Gly266Val) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 18, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000220597.7

Allele description [Variation Report for NM_000546.6(TP53):c.797G>T (p.Gly266Val)]

NM_000546.6(TP53):c.797G>T (p.Gly266Val)

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>T (p.Gly266Val)

HGVS:

NC_000017.11:g.7673823C>A
NG_017013.2:g.18728G>T
NM_000546.6:c.797G>TMANE SELECT
NM_001126112.3:c.797G>T
NM_001126113.3:c.797G>T
NM_001126114.3:c.797G>T
NM_001126115.2:c.401G>T
NM_001126116.2:c.401G>T
NM_001126117.2:c.401G>T
NM_001126118.2:c.680G>T
NM_001276695.3:c.680G>T
NM_001276696.3:c.680G>T
NM_001276697.3:c.320G>T
NM_001276698.3:c.320G>T
NM_001276699.3:c.320G>T
NM_001276760.3:c.680G>T
NM_001276761.3:c.680G>T
NP_000537.3:p.Gly266Val
NP_001119584.1:p.Gly266Val
NP_001119585.1:p.Gly266Val
NP_001119586.1:p.Gly266Val
NP_001119587.1:p.Gly134Val
NP_001119588.1:p.Gly134Val
NP_001119589.1:p.Gly134Val
NP_001119590.1:p.Gly227Val
NP_001263624.1:p.Gly227Val
NP_001263625.1:p.Gly227Val
NP_001263626.1:p.Gly107Val
NP_001263627.1:p.Gly107Val
NP_001263628.1:p.Gly107Val
NP_001263689.1:p.Gly227Val
NP_001263690.1:p.Gly227Val
LRG_321:g.18728G>T
NC_000017.10:g.7577141C>A
NM_000546.4:c.797G>T
P04637:p.Gly266Val

Protein change:

G107V

Links:

UniProtKB: P04637#VAR_045326; dbSNP: rs193920774

NCBI 1000 Genomes Browser:

rs193920774

Molecular consequence:

NM_000546.6:c.797G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.797G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.797G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.797G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.401G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.401G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.401G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.680G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.680G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.680G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.320G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.320G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.320G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.680G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.680G>T - 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
SCV000277650	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 12, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10519380, 11593407 Citation Link,
SCV002581995	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (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

SCV000277650

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 12, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV002581995

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(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

Dominant-negative mutations of the tumor suppressor p53 relating to early onset of glioblastoma multiforme.

Marutani M, Tonoki H, Tada M, Takahashi M, Kashiwazaki H, Hida Y, Hamada J, Asaka M, Moriuchi T.

Cancer Res. 1999 Oct 1;59(19):4765-9.

PubMed [citation]

PMID:: 10519380

A "no-hybrids" screen for functional antagonizers of human p53 transactivator function: dominant negativity in fission yeast.

Waddell S, Jenkins JR, Proikas-Cezanne T.

Oncogene. 2001 Sep 20;20(42):6001-8.

PubMed [citation]

PMID:: 11593407

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000277650.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.G266V pathogenic mutation (also known as c.797G>T), located in coding exon 7 of the TP53 gene, results from a G to T substitution at nucleotide position 797. The glycine at codon 266 is replaced by valine, an amino acid with dissimilar properties. This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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). 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.G266E ( c.797G>A), has been detected an individuals meeting Chompret criteria (Ambry internal data). 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, SCV002581995.1

#	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: Jun 23, 2024

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