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NM_000546.6(TP53):c.817C>A (p.Arg273Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Jun 18, 2022
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:
RCV000561782.6

Allele description [Variation Report for NM_000546.6(TP53):c.817C>A (p.Arg273Ser)]

NM_000546.6(TP53):c.817C>A (p.Arg273Ser)

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.817C>A (p.Arg273Ser)
HGVS:
  • NC_000017.11:g.7673803G>T
  • NG_017013.2:g.18748C>A
  • NM_000546.6:c.817C>AMANE SELECT
  • NM_001126112.3:c.817C>A
  • NM_001126113.3:c.817C>A
  • NM_001126114.3:c.817C>A
  • NM_001126115.2:c.421C>A
  • NM_001126116.2:c.421C>A
  • NM_001126117.2:c.421C>A
  • NM_001126118.2:c.700C>A
  • NM_001276695.3:c.700C>A
  • NM_001276696.3:c.700C>A
  • NM_001276697.3:c.340C>A
  • NM_001276698.3:c.340C>A
  • NM_001276699.3:c.340C>A
  • NM_001276760.3:c.700C>A
  • NM_001276761.3:c.700C>A
  • NP_000537.3:p.Arg273Ser
  • NP_000537.3:p.Arg273Ser
  • NP_001119584.1:p.Arg273Ser
  • NP_001119585.1:p.Arg273Ser
  • NP_001119586.1:p.Arg273Ser
  • NP_001119587.1:p.Arg141Ser
  • NP_001119588.1:p.Arg141Ser
  • NP_001119589.1:p.Arg141Ser
  • NP_001119590.1:p.Arg234Ser
  • NP_001263624.1:p.Arg234Ser
  • NP_001263625.1:p.Arg234Ser
  • NP_001263626.1:p.Arg114Ser
  • NP_001263627.1:p.Arg114Ser
  • NP_001263628.1:p.Arg114Ser
  • NP_001263689.1:p.Arg234Ser
  • NP_001263690.1:p.Arg234Ser
  • LRG_321t1:c.817C>A
  • LRG_321:g.18748C>A
  • LRG_321p1:p.Arg273Ser
  • NC_000017.10:g.7577121G>T
  • NM_000546.4:c.817C>A
  • NM_000546.5:c.817C>A
Protein change:
R114S
Links:
dbSNP: rs121913343
NCBI 1000 Genomes Browser:
rs121913343
Molecular consequence:
  • NM_000546.6:c.817C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.817C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.817C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.817C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.2:c.421C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.2:c.421C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.2:c.421C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.700C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.700C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.700C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.3:c.340C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.3:c.340C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.3:c.340C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.700C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.700C>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000664439Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Dec 21, 2021) 		germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

Citation Link,

SCV002582454Genome-Nilou Lab
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jun 18, 2022) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenonot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Integrating mutation data and structural analysis of the TP53 tumor-suppressor protein.

Martin AC, Facchiano AM, Cuff AL, Hernandez-Boussard T, Olivier M, Hainaut P, Thornton JM.

Hum Mutat. 2002 Feb;19(2):149-64.

PubMed [citation]
PMID:
11793474

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
See all PubMed Citations (13)

Details of each submission

From Ambry Genetics, SCV000664439.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

The p.R273S pathogenic mutation (also known as c.817C>A), located in coding exon 7 of the TP53 gene, results from a C to A substitution at nucleotide position 817. The arginine at codon 273 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. This pathogenic mutation has been reported as a germline mutation in 1 of 235 unselected pediatric patients with osteosarcoma, as well as in a family meeting classic LFS criteria and a patient with early-onset breast cancer meeting Chompret criteria (McIntyre JF et al. J. Clin. Oncol., 1994 May;12:925-30; Tabori U et al. Cancer Res, 2007 Feb;67:1415-8; Petry V et al. Fam Cancer, 2020 01;19:47-53). This alteration occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain, and has repeatedly shown loss of transactivation capacity in yeast-based functional studies (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Mitsumoto Y et al. Hum. Pathol., 2004 Mar;35:350-6; Monti P et al. Oncogene, 2003 Aug;22:5252-60; Monti P et al. Mol. Cancer Res., 2011 Mar;9:271-9). 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 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 alteration has been described as “oncomorphic”, or gain-of-function, secondary to functional analysis indicating a loss of interaction with the microprocessing Drosha complex (Brachova P et al. J Cancer Ther, 2014 Jun;5:506-516). Further, crystal structure analysis indicates this position is involved in DNA contact and binding (Martin A et al., Hum. Mutat. 2002 Feb; 19(2):149-64). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, p.R273S is classified as a pathogenic mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Genome-Nilou Lab, SCV002582454.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024