NM_000546.6(TP53):c.776A>T (p.Asp259Val) 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:: RCV000563029.7

Allele description [Variation Report for NM_000546.6(TP53):c.776A>T (p.Asp259Val)]

NM_000546.6(TP53):c.776A>T (p.Asp259Val)

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.776A>T (p.Asp259Val)

HGVS:

NC_000017.11:g.7674187T>A
NG_017013.2:g.18364A>T
NM_000546.6:c.776A>TMANE SELECT
NM_001126112.3:c.776A>T
NM_001126113.3:c.776A>T
NM_001126114.3:c.776A>T
NM_001126115.2:c.380A>T
NM_001126116.2:c.380A>T
NM_001126117.2:c.380A>T
NM_001126118.2:c.659A>T
NM_001276695.3:c.659A>T
NM_001276696.3:c.659A>T
NM_001276697.3:c.299A>T
NM_001276698.3:c.299A>T
NM_001276699.3:c.299A>T
NM_001276760.3:c.659A>T
NM_001276761.3:c.659A>T
NP_000537.3:p.Asp259Val
NP_000537.3:p.Asp259Val
NP_001119584.1:p.Asp259Val
NP_001119585.1:p.Asp259Val
NP_001119586.1:p.Asp259Val
NP_001119587.1:p.Asp127Val
NP_001119588.1:p.Asp127Val
NP_001119589.1:p.Asp127Val
NP_001119590.1:p.Asp220Val
NP_001263624.1:p.Asp220Val
NP_001263625.1:p.Asp220Val
NP_001263626.1:p.Asp100Val
NP_001263627.1:p.Asp100Val
NP_001263628.1:p.Asp100Val
NP_001263689.1:p.Asp220Val
NP_001263690.1:p.Asp220Val
LRG_321t1:c.776A>T
LRG_321:g.18364A>T
LRG_321p1:p.Asp259Val
NC_000017.10:g.7577505T>A
NM_000546.4:c.776A>T
NM_000546.5:c.776A>T

Protein change:

D100V

Links:

dbSNP: rs745425759

NCBI 1000 Genomes Browser:

rs745425759

Molecular consequence:

NM_000546.6:c.776A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.776A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.776A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.776A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.380A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.380A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.380A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.659A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.659A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.659A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.299A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.299A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.299A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.659A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.659A>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
SCV000672397	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 12, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11051241, 11429700, 11429705, 11896595, 12917626, 20407015 Citation Link,
SCV002581998	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

SCV000672397

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 12, 2021)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV002581998

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

Functional evaluation of p53 and PTEN gene mutations in gliomas.

Kato H, Kato S, Kumabe T, Sonoda Y, Yoshimoto T, Kato S, Han SY, Suzuki T, Shibata H, Kanamaru R, Ishioka C.

Clin Cancer Res. 2000 Oct;6(10):3937-43.

PubMed [citation]

PMID:: 11051241

Amifostine (WR2721) restores transcriptional activity of specific p53 mutant proteins in a yeast functional assay.

Maurici D, Monti P, Campomenosi P, North S, Frebourg T, Fronza G, Hainaut P.

Oncogene. 2001 Jun 14;20(27):3533-40.

PubMed [citation]

PMID:: 11429700

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000672397.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.D259V pathogenic mutation (also known as c.776A>T), located in coding exon 6 of the TP53 gene, results from an A to T substitution at nucleotide position 776. The aspartic acid at codon 259 is replaced by valine, an amino acid with highly dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9, Maurici D et al. Oncogene, 2001 Jun;20:3533-40; Campomenosi P et al. Oncogene, 2001 Jun;20:3573-9; Monti P et al. Oncogene, 2003 Aug;22:5252-60; Jordan JJ et al. Mol. Cancer Res., 2010 May;8:701-16). 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). This amino acid position is highly conserved through mammals but not in all 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, SCV002581998.1

#	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 10, 2024

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