NM_000546.5(TP53):c.659A>G (p.Tyr220Cys) AND Li-Fraumeni syndrome

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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 4, 2016
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000232050.2

Allele description

NM_000546.5(TP53):c.659A>G (p.Tyr220Cys)

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.659A>G (p.Tyr220Cys)

Other names:

p.Y220C:TAT>TGT

HGVS:

NC_000017.11:g.7674872T>C
NG_017013.2:g.17679A>G
NM_000546.5:c.659A>G
NM_001126112.2:c.659A>G
NM_001126113.2:c.659A>G
NM_001126114.2:c.659A>G
NM_001126115.1:c.263A>G
NM_001126116.1:c.263A>G
NM_001126117.1:c.263A>G
NM_001126118.1:c.542A>G
NP_000537.3:p.Tyr220Cys
NP_001119584.1:p.Tyr220Cys
NP_001119585.1:p.Tyr220Cys
NP_001119586.1:p.Tyr220Cys
NP_001119587.1:p.Tyr88Cys
NP_001119588.1:p.Tyr88Cys
NP_001119589.1:p.Tyr88Cys
NP_001119590.1:p.Tyr181Cys
LRG_321t1:c.659A>G
LRG_321t2:c.659A>G
LRG_321t3:c.659A>G
LRG_321t4:c.659A>G
LRG_321t5:c.263A>G
LRG_321t6:c.263A>G
LRG_321t7:c.263A>G
LRG_321t8:c.542A>G
LRG_321:g.17679A>G
LRG_321p1:p.Tyr220Cys
LRG_321p3:p.Tyr220Cys
LRG_321p4:p.Tyr220Cys
LRG_321p5:p.Tyr88Cys
LRG_321p6:p.Tyr88Cys
LRG_321p7:p.Tyr88Cys
LRG_321p8:p.Tyr181Cys
NC_000017.10:g.7578190T>C
NM_000546.4:c.659A>G
P04637:p.Tyr220Cys
p.Y220C

Protein change:

Y181C

Links:

UniProtKB: P04637#VAR_005957; dbSNP: rs121912666

NCBI 1000 Genomes Browser:

rs121912666

Allele Frequency:

0.00003(C)

Molecular consequence:

NM_000546.5:c.659A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Li-Fraumeni syndrome (LFS)
Synonyms:: Sarcoma family syndrome of Li and Fraumeni
Identifiers:: MedGen: C0085390; OMIM: PS151623

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000285206	Invitae,	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 4, 2016)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000285206

Invitae,

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 4, 2016)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Invitae,, SCV000285206.2

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

Description

This sequence change replaces tyrosine with cysteine at codon 220 of the TP53 protein (p.Tyr220Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs121912666, ExAC <0.01%). This variant has been reported as de novo in an individual with Li-Fraumeni syndrome (LFS) (PMID: 18307025), as well as in individuals with breast cancer and adrenal carcinoma (PMID: 21761402, 20805372). This variant has also been reported to segregate with LFS in several families (PMID: 8118819, 10432928, 19101993). ClinVar contains an entry for this variant (Variation ID: 127819). Experimental studies have shown that this missense change destabilizes the TP53 protein, and disrupts its DNA binding and transactivation activity (PMID: 20128691, 21343334, 22923379, 17015838). Many of these properties are reversed in cell culture by treatment with a small molecule (PMID: 23630318). For these reasons, this variant has been classified as Pathogenic.

#	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: Dec 19, 2017

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