NM_000546.6(TP53):c.844C>T (p.Arg282Trp) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 21, 2021
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:: RCV000236400.15

Allele description [Variation Report for NM_000546.6(TP53):c.844C>T (p.Arg282Trp)]

NM_000546.6(TP53):c.844C>T (p.Arg282Trp)

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.844C>T (p.Arg282Trp)

HGVS:

NC_000017.11:g.7673776G>A
NG_017013.2:g.18775C>T
NM_000546.6:c.844C>TMANE SELECT
NM_001126112.3:c.844C>T
NM_001126113.3:c.844C>T
NM_001126114.3:c.844C>T
NM_001126115.2:c.448C>T
NM_001126116.2:c.448C>T
NM_001126117.2:c.448C>T
NM_001126118.2:c.727C>T
NM_001276695.3:c.727C>T
NM_001276696.3:c.727C>T
NM_001276697.3:c.367C>T
NM_001276698.3:c.367C>T
NM_001276699.3:c.367C>T
NM_001276760.3:c.727C>T
NM_001276761.3:c.727C>T
NP_000537.3:p.Arg282Trp
NP_000537.3:p.Arg282Trp
NP_001119584.1:p.Arg282Trp
NP_001119585.1:p.Arg282Trp
NP_001119586.1:p.Arg282Trp
NP_001119587.1:p.Arg150Trp
NP_001119588.1:p.Arg150Trp
NP_001119589.1:p.Arg150Trp
NP_001119590.1:p.Arg243Trp
NP_001263624.1:p.Arg243Trp
NP_001263625.1:p.Arg243Trp
NP_001263626.1:p.Arg123Trp
NP_001263627.1:p.Arg123Trp
NP_001263628.1:p.Arg123Trp
NP_001263689.1:p.Arg243Trp
NP_001263690.1:p.Arg243Trp
LRG_321t1:c.844C>T
LRG_321:g.18775C>T
LRG_321p1:p.Arg282Trp
NC_000017.10:g.7577094G>A
NM_000546.4:c.844C>T
NM_000546.5:c.844C>T
NM_000546.5:c.[844C>T]
P04637:p.Arg282Trp

Protein change:

R123W; ARG282TRP

Links:

UniProtKB: P04637#VAR_006016; OMIM: 191170.0018; dbSNP: rs28934574

NCBI 1000 Genomes Browser:

rs28934574

Molecular consequence:

NM_000546.6:c.844C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.844C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.844C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.844C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.448C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.448C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.448C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.727C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.727C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.727C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.367C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.367C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.367C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.727C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.727C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000292698	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 21, 2021)	germline	clinical testing	Citation Link,
SCV000692065	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Pathogenic	unknown	clinical testing
SCV002069228	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 8, 2018)	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

SCV000292698

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(May 21, 2021)

germline

clinical testing

Citation Link,

SCV000692065

Mayo Clinic Laboratories, Mayo Clinic

no assertion criteria provided

Pathogenic

unknown

clinical testing

SCV002069228

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 8, 2018)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000292698.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato et al., 2003; Scian et al., 2004; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32658383, 32475984, 31980526, 31105275, 32098966, 31537539, 31081129, 31159747, 30840781, 31016814, 30720243, 30709381, 28472496, 25186627, 28975465, 29555771, 29752822, 28861920, 29581140, 15280671, 29979965, 29315962, 29506128, 29300620, 29237527, 27882657, 28534505, 27683180, 28091804, 28369373, 27680515, 28387325, 28527674, 27077130, 28397142, 25925845, 8402598, 19468865, 18669439, 1349175, 8425176, 10864200, 21761402, 22672556, 27501770, 27714481, 27619989, 26911350, 25385265, 26878390, 26014290, 25619955, 15077194, 21343334, 21305319, 25637381, 24651015, 24573247, 14583457, 16206219, 1565144, 25584008, 19012332, 11370630, 21059199, 1565143, 12517413, 21445056, 12917626, 12826609, 16861262, 1631137, 17606709)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV000692065.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002069228.1

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

Description

DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.844C>T, in exon 8 that results in an amino acid change, p.Arg282Trp. The p.Arg282Trp change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg282Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in the EXAC database with a low population frequency of 0.002% (dbSNP rs28934574). The p.Arg282Trp pathogenic sequence change has previously been described in multiple unrelated individuals with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome, and has been observed in the de novo state in at least two affected individuals (Malkin et al., 1992; Bougeard et al., 2001; Pinto et al., 2009; Wu et al., 2011; Kast et al., 2012; Melhem-Bertrandt et al., 2012; Wasserman et al., 2015). Functional studies have provided evidence that the p.Arg282Trp sequence change has a dominant negative effect and leads to significantly reduced TP53 transcriptional activity in response to DNA damage (Zerdoumi et al., 2017).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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