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NM_000546.6(TP53):c.536A>G (p.His179Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Mar 1, 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:
RCV001023983.12

Allele description [Variation Report for NM_000546.6(TP53):c.536A>G (p.His179Arg)]

NM_000546.6(TP53):c.536A>G (p.His179Arg)

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.536A>G (p.His179Arg)
HGVS:
  • NC_000017.11:g.7675076T>C
  • NG_017013.2:g.17475A>G
  • NM_000546.6:c.536A>GMANE SELECT
  • NM_001126112.3:c.536A>G
  • NM_001126113.3:c.536A>G
  • NM_001126114.3:c.536A>G
  • NM_001126115.2:c.140A>G
  • NM_001126116.2:c.140A>G
  • NM_001126117.2:c.140A>G
  • NM_001126118.2:c.419A>G
  • NM_001276695.3:c.419A>G
  • NM_001276696.3:c.419A>G
  • NM_001276697.3:c.59A>G
  • NM_001276698.3:c.59A>G
  • NM_001276699.3:c.59A>G
  • NM_001276760.3:c.419A>G
  • NM_001276761.3:c.419A>G
  • NP_000537.3:p.His179Arg
  • NP_000537.3:p.His179Arg
  • NP_001119584.1:p.His179Arg
  • NP_001119585.1:p.His179Arg
  • NP_001119586.1:p.His179Arg
  • NP_001119587.1:p.His47Arg
  • NP_001119588.1:p.His47Arg
  • NP_001119589.1:p.His47Arg
  • NP_001119590.1:p.His140Arg
  • NP_001263624.1:p.His140Arg
  • NP_001263625.1:p.His140Arg
  • NP_001263626.1:p.His20Arg
  • NP_001263627.1:p.His20Arg
  • NP_001263628.1:p.His20Arg
  • NP_001263689.1:p.His140Arg
  • NP_001263690.1:p.His140Arg
  • LRG_321t1:c.536A>G
  • LRG_321t3:c.536A>G
  • LRG_321:g.17475A>G
  • LRG_321p1:p.His179Arg
  • NC_000017.10:g.7578394T>C
  • NM_000546.4:c.536A>G
  • NM_000546.5:c.536A>G
Protein change:
H140R
Links:
dbSNP: rs1057519991
NCBI 1000 Genomes Browser:
rs1057519991
Molecular consequence:
  • NM_000546.6:c.536A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.3:c.536A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.3:c.536A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.3:c.536A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.2:c.140A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.2:c.140A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.2:c.140A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.2:c.419A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.3:c.419A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.3:c.419A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.3:c.59A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.3:c.59A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.3:c.59A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.3:c.419A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.3:c.419A>G - 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
SCV001185932Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Feb 1, 2023) 		germlineclinical testing

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

Citation Link,

SCV001348246Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Mar 1, 2023) 		germlineclinical testing

PubMed (10)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot 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

p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis.

Bergamaschi D, Gasco M, Hiller L, Sullivan A, Syed N, Trigiante G, Yulug I, Merlano M, Numico G, Comino A, Attard M, Reelfs O, Gusterson B, Bell AK, Heath V, Tavassoli M, Farrell PJ, Smith P, Lu X, Crook T.

Cancer Cell. 2003 Apr;3(4):387-402.

PubMed [citation]
PMID:
12726864
See all PubMed Citations (16)

Details of each submission

From Ambry Genetics, SCV001185932.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The p.H179R variant (also known as c.536A>G), located in coding exon 4 of the TP53 gene, results from an A to G substitution at nucleotide position 536. The histidine at codon 179 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported as a somatic mutation 174 times in various tumors by the IARC TP53 database, and as a germline mutation in probands meeting Chompret criteria (Ambry internal data; Petitjean A et al. IARC TP53 database [version R19, August 2018]. Hum Mutat. 2007 Jun;28(6):622-9). This alteration is located in the DNA binding domain, and is one of four residues necessary to bind the zinc molecule that stabilizes the beta sheet structure of the protein (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). Numerous functional studies in yeast cells have demonstrated this alteration is deficient in transactivation activity and exhibits a dominant negative effect (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9, Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98; Hassan NM et al. Cancer Lett. 2008 Oct; 270(1):108-19). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and 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). Functional studies in mammalian cells have shown gain of function activities for p.H179R, including interference with the p73 apoptotic pathway and the TGF-B tumor supressor signaling pathway (Kalo E et al. Mol. Cell. Biol. 2007 Dec; 27(23):8228-42; Bergamaschi D et al. Cancer Cell 2003 Apr; 3(4):387-402). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). In addition, another alteration at this same position, p.H179Q was identified as a de novo mutation in a patient with two Li-Fraumeni core cancers (Gonzalez KD et al. J. Med. Genet. 2009 Oct; 46(10):689-93). 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.

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

From Color Diagnostics, LLC DBA Color Health, SCV001348246.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (10)

Description

This missense variant replaces histidine with arginine at codon 179 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental studies have shown that this variant is partially functional in yeast transactivation assays, non-functional in human cell proliferation assays, and exhibits dominant-negative effect and loss of function in human cell growth suppression assays (PMID: 12826609, 16778209, 17311302, 22427690, 26585234, 30224644, 32980694). This variant has been reported in individuals affected with early-onset breast cancer meeting Chompret criteria (PMID: 33138793, 35820297; IARC Database) and in an individual affected with choroid plexus carcinoma (PMCID: PMC9164685). Two different missense variants at the same amino acid positions, H179Q and H179Y, are established pathogenic variants (ClinVar variation ID 127815, 376607, 406578). This variant has been identified in 1/251340 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

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

Last Updated: Nov 10, 2024