NM_000546.5(TP53):c.848G>A (p.Arg283His) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Aug 15, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000213060.4

Allele description [Variation Report for NM_000546.5(TP53):c.848G>A (p.Arg283His)]

NM_000546.5(TP53):c.848G>A (p.Arg283His)

Gene:
TP53:tumor protein p53 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p13.1
Genomic location:
Preferred name:
NM_000546.5(TP53):c.848G>A (p.Arg283His)
Other names:
p.R283H:CGC>CAC
HGVS:
  • NC_000017.11:g.7673772C>T
  • NG_017013.2:g.18779G>A
  • NM_000546.5:c.848G>A
  • NM_001126112.2:c.848G>A
  • NM_001126113.2:c.848G>A
  • NM_001126114.2:c.848G>A
  • NM_001126115.1:c.452G>A
  • NM_001126116.1:c.452G>A
  • NM_001126117.1:c.452G>A
  • NM_001126118.1:c.731G>A
  • NM_001276695.2:c.731G>A
  • NM_001276696.2:c.731G>A
  • NM_001276697.2:c.371G>A
  • NM_001276698.2:c.371G>A
  • NM_001276699.2:c.371G>A
  • NM_001276760.2:c.731G>A
  • NM_001276761.2:c.731G>A
  • NP_000537.3:p.Arg283His
  • NP_001119584.1:p.Arg283His
  • NP_001119585.1:p.Arg283His
  • NP_001119586.1:p.Arg283His
  • NP_001119587.1:p.Arg151His
  • NP_001119588.1:p.Arg151His
  • NP_001119589.1:p.Arg151His
  • NP_001119590.1:p.Arg244His
  • NP_001263624.1:p.Arg244His
  • NP_001263625.1:p.Arg244His
  • NP_001263626.1:p.Arg124His
  • NP_001263627.1:p.Arg124His
  • NP_001263628.1:p.Arg124His
  • NP_001263689.1:p.Arg244His
  • NP_001263690.1:p.Arg244His
  • LRG_321t1:c.848G>A
  • LRG_321t2:c.848G>A
  • LRG_321t3:c.848G>A
  • LRG_321t4:c.848G>A
  • LRG_321t5:c.452G>A
  • LRG_321t6:c.452G>A
  • LRG_321t7:c.452G>A
  • LRG_321t8:c.731G>A
  • LRG_321:g.18779G>A
  • LRG_321:p.Arg283His
  • LRG_321p1:p.Arg283His
  • LRG_321p3:p.Arg283His
  • LRG_321p4:p.Arg283His
  • LRG_321p5:p.Arg151His
  • LRG_321p6:p.Arg151His
  • LRG_321p7:p.Arg151His
  • LRG_321p8:p.Arg244His
  • NC_000017.10:g.7577090C>T
  • NM_000546.4:c.848G>A
  • P04637:p.Arg283His
  • p.R283H
Protein change:
R124H
Links:
UniProtKB: P04637#VAR_006019; dbSNP: rs371409680
NCBI 1000 Genomes Browser:
rs371409680
Molecular consequence:
  • NM_000546.5:c.848G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126112.2:c.848G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126113.2:c.848G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126114.2:c.848G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126115.1:c.452G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126116.1:c.452G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126117.1:c.452G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001126118.1:c.731G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276695.2:c.731G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276696.2:c.731G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276697.2:c.371G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276698.2:c.371G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276699.2:c.371G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276760.2:c.731G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276761.2:c.731G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000211762GeneDxcriteria provided, single submitter
Uncertain significance
(Aug 15, 2018)
germlineclinical testing

Citation Link,

SCV000602281Quest Diagnostics Nichols Institute San Juan Capistranocriteria provided, single submitter
Likely pathogenic
(Oct 12, 2016)
germlineclinical testing

PubMed (21)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Inhibiting MDM2-p53 Interaction Suppresses Tumor Growth in Patient-Derived Non-Small Cell Lung Cancer Xenograft Models.

Hai J, Sakashita S, Allo G, Ludkovski O, Ng C, Shepherd FA, Tsao MS.

J Thorac Oncol. 2015 Aug;10(8):1172-80. doi: 10.1097/JTO.0000000000000584.

PubMed [citation]
PMID:
26200271

Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database.

Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M.

Hum Mutat. 2007 Jun;28(6):622-9.

PubMed [citation]
PMID:
17311302
See all PubMed Citations (21)

Details of each submission

From GeneDx, SCV000211762.12

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant is denoted TP53 c.848G>A at the cDNA level, p.Arg283His (R283H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been reported as a germline finding in an individual with an astrocytoma (Ishii 1999). Although this variant is reported having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003), multiple other studies have revealed contradictory results. With the exception of the BAX reporter, transactivation of typical p53 response elements has been found to be either normal or partially present across multiple studies (Crook 1998, Di Como 1998, Flaman 1998, Robert 2000, Campomenosi 2001, Gaiddon 2001, Maurici 2001, Fulci 2002, Monti 2002, Resnick 2003, Dearth 2007, Monti 2011). With respect to BAX, an important regulator of apoptotic activity, most, but not all, studies have revealed decreased transactivation of this specific response element. However, TP53 Arg283His has not been shown to impact apoptotic activity, and results from colony formation and growth suppression assays have also been comparable to wild type (Crook 1998, Fulci 2002, Kotler 2018). TP53 Arg283His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on conflicting functional evidence as well as a lack of individuals with histories suspicious for Li-Fraumeni syndrome in the published literature and our internal laboratory cases, we consider TP53 Arg283His to be a variant of uncertain significance.

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000602281.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (21)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 27, 2021

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