NM_000546.5(TP53):c.847C>T (p.Arg283Cys) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 22, 2018
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:: RCV000585912.1

Allele description

NM_000546.5(TP53):c.847C>T (p.Arg283Cys)

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.847C>T (p.Arg283Cys)

Other names:

p.R283C:CGC>TGC

HGVS:

NC_000017.11:g.7673773G>A
NG_017013.2:g.18778C>T
NM_000546.5:c.847C>T
NM_001126112.2:c.847C>T
NM_001126113.2:c.847C>T
NM_001126114.2:c.847C>T
NM_001126115.1:c.451C>T
NM_001126116.1:c.451C>T
NM_001126117.1:c.451C>T
NM_001126118.1:c.730C>T
NP_000537.3:p.Arg283Cys
NP_001119584.1:p.Arg283Cys
NP_001119585.1:p.Arg283Cys
NP_001119586.1:p.Arg283Cys
NP_001119587.1:p.Arg151Cys
NP_001119588.1:p.Arg151Cys
NP_001119589.1:p.Arg151Cys
NP_001119590.1:p.Arg244Cys
LRG_321t1:c.847C>T
LRG_321t2:c.847C>T
LRG_321t3:c.847C>T
LRG_321t4:c.847C>T
LRG_321t5:c.451C>T
LRG_321t6:c.451C>T
LRG_321t7:c.451C>T
LRG_321t8:c.730C>T
LRG_321:g.18778C>T
LRG_321p1:p.Arg283Cys
LRG_321p3:p.Arg283Cys
LRG_321p4:p.Arg283Cys
LRG_321p5:p.Arg151Cys
LRG_321p6:p.Arg151Cys
LRG_321p7:p.Arg151Cys
LRG_321p8:p.Arg244Cys
NC_000017.10:g.7577091G>A
NM_000546.4:c.847C>T
P04637:p.Arg283Cys
p.R283C

Protein change:

R151C

Links:

UniProtKB: P04637#VAR_006017; dbSNP: rs149633775

NCBI 1000 Genomes Browser:

rs149633775

Molecular consequence:

NM_000546.5:c.847C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:: MedGen: CN517202

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149648	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Jan 3, 2018)	germline	clinical testing	Citation Link,
SCV000697452	Integrated Genetics/Laboratory Corporation of America	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Nov 18, 2016)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 23894400, 17224268, 19367569, 8203469, 26086041, 21343334, 25637381, 15173255, 24868540, 21761402, 21232794 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000889883	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest pathogenicity assessment criteria)	Uncertain significance (Jan 22, 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

SCV000149648

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Jan 3, 2018)

germline

clinical testing

Citation Link,

SCV000697452

Integrated Genetics/Laboratory Corporation of America

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Nov 18, 2016)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000889883

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest pathogenicity assessment criteria)

Uncertain significance
(Jan 22, 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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

High frequency of germline TP53 mutations in a prospective adult-onset sarcoma cohort.

Mitchell G, Ballinger ML, Wong S, Hewitt C, James P, Young MA, Cipponi A, Pang T, Goode DL, Dobrovic A, Thomas DM; International Sarcoma Kindred Study.

PLoS One. 2013 Jul 22;8(7):e69026. doi: 10.1371/journal.pone.0069026. Print 2013.

PubMed [citation]

PMID:: 23894400
PMCID:: PMC3718831

Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families.

Manoukian S, Peissel B, Pensotti V, Barile M, Cortesi L, Stacchiotti S, Terenziani M, Barbera F, Pasquini G, Frigerio S, Pierotti MA, Radice P, Della-Torre G.

Eur J Cancer. 2007 Feb;43(3):601-6. Epub 2007 Jan 16.

PubMed [citation]

PMID:: 17224268

See all PubMed Citations (12)

Details of each submission

From GeneDx, SCV000149648.13

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

Description

This variant is denoted TP53 c.847C>T at the cDNA level, p.Arg283Cys (R283C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been reported in at least five individuals with various cancers, none of whom met Li-Fraumeni syndrome criteria, as well as at least two healthy controls (Keller 2004, Pekova 2011, Schulz 2012, Melhem-Bertrandt 2012, Bodian 2013, Mitchell 2013, Yurgelun 2015). TP53 Arg283Cys was also observed in a woman with a personal history of breast cancer and leiomyosarcoma who met Chompret criteria; however, she was also found to harbor a truncating BRCA2 variant (Manoukian 2007). Functional studies have identified both normal and reduced transcriptional activity for a variety of reporters, with no evidence for a dominant-negative effect (Pekova 2011, Monti 2011, Jagosova 2012). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg283Cys was observed at an allele frequency of 0.02% (20/126,682) in individuals of European ancestry 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 currently available evidence, it is unclear whether TP53 Arg283Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

#	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 Integrated Genetics/Laboratory Corporation of America, SCV000697452.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

Variant summary: The TP53 c.847C>T (p.Arg283Cys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (MutationTaster was not captured due to low p-value). 2/5 splice prediction tools and at least one literature (Kouidou_2009) predict that this variant may create a novel 5' splicing donor site. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant has been reported in patients with CLL, Early-Onset Colorectal Cancer, breast cancer, gastric carcinoma, brain tumor as germline or somatic variant. One patient with metachronous breast cancers and a subsequent leiomyosarcoma carries this variant and a pathogenic BRCA2 variant (p.Arg2394X). This variant was found in 14/120734 control chromosomes at a frequency of 0.000116, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000469). However, some occurrences in control population may be somatic occurrences in cancer patients, thus the possibility that this variant is pathogenic can not be ruled out based on the allele frequency in controls. Two functional studies in yeast provide conflicting results (no defect/Pekova_2011 and partially defect/Monti_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.

#	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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000889883.1

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

#	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: Mar 14, 2019

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