NM_000546.6(TP53):c.840A>T (p.Arg280Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 8, 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:: RCV002447244.2

Allele description [Variation Report for NM_000546.6(TP53):c.840A>T (p.Arg280Ser)]

NM_000546.6(TP53):c.840A>T (p.Arg280Ser)

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.840A>T (p.Arg280Ser)

HGVS:

NC_000017.11:g.7673780T>A
NG_017013.2:g.18771A>T
NM_000546.6:c.840A>TMANE SELECT
NM_001126112.3:c.840A>T
NM_001126113.3:c.840A>T
NM_001126114.3:c.840A>T
NM_001126115.2:c.444A>T
NM_001126116.2:c.444A>T
NM_001126117.2:c.444A>T
NM_001126118.2:c.723A>T
NM_001276695.3:c.723A>T
NM_001276696.3:c.723A>T
NM_001276697.3:c.363A>T
NM_001276698.3:c.363A>T
NM_001276699.3:c.363A>T
NM_001276760.3:c.723A>T
NM_001276761.3:c.723A>T
NP_000537.3:p.Arg280Ser
NP_001119584.1:p.Arg280Ser
NP_001119585.1:p.Arg280Ser
NP_001119586.1:p.Arg280Ser
NP_001119587.1:p.Arg148Ser
NP_001119588.1:p.Arg148Ser
NP_001119589.1:p.Arg148Ser
NP_001119590.1:p.Arg241Ser
NP_001263624.1:p.Arg241Ser
NP_001263625.1:p.Arg241Ser
NP_001263626.1:p.Arg121Ser
NP_001263627.1:p.Arg121Ser
NP_001263628.1:p.Arg121Ser
NP_001263689.1:p.Arg241Ser
NP_001263690.1:p.Arg241Ser
LRG_321:g.18771A>T
NC_000017.10:g.7577098T>A
NM_000546.4:c.840A>T

Protein change:

R121S

Links:

dbSNP: rs1567547687

NCBI 1000 Genomes Browser:

rs1567547687

Molecular consequence:

NM_000546.6:c.840A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.840A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.840A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.840A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.444A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.444A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.444A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.723A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.723A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.723A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.363A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.363A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.363A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.723A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.723A>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
SCV002677755	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 8, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12826609, 29489754, 29979965, 30224644 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002677755

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 8, 2021)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

The landscape of genomic alterations across childhood cancers.

Gröbner SN, Worst BC, Weischenfeldt J, Buchhalter I, Kleinheinz K, Rudneva VA, Johann PD, Balasubramanian GP, Segura-Wang M, Brabetz S, Bender S, Hutter B, Sturm D, Pfaff E, Hübschmann D, Zipprich G, Heinold M, Eils J, Lawerenz C, Erkek S, Lambo S, Waszak S, et al.

Nature. 2018 Mar 15;555(7696):321-327. doi: 10.1038/nature25480. Epub 2018 Feb 28. Erratum in: Nature. 2018 Jul;559(7714):E10. doi: 10.1038/s41586-018-0167-2.

PubMed [citation]

PMID:: 29489754

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV002677755.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.R280S pathogenic mutation (also known as c.840A>T), located in coding exon 7 of the TP53 gene, results from an A to T substitution at nucleotide position 840. The arginine at codon 280 is replaced by serine, an amino acid with dissimilar 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). 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 in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Last Updated: May 7, 2024

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