NM_000546.6(TP53):c.661G>A (p.Glu221Lys) AND Li-Fraumeni syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 13, 2022
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:: RCV000528158.19

Allele description [Variation Report for NM_000546.6(TP53):c.661G>A (p.Glu221Lys)]

NM_000546.6(TP53):c.661G>A (p.Glu221Lys)

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.661G>A (p.Glu221Lys)

HGVS:

NC_000017.11:g.7674870C>T
NG_017013.2:g.17681G>A
NM_000546.6:c.661G>AMANE SELECT
NM_001126112.3:c.661G>A
NM_001126113.3:c.661G>A
NM_001126114.3:c.661G>A
NM_001126115.2:c.265G>A
NM_001126116.2:c.265G>A
NM_001126117.2:c.265G>A
NM_001126118.2:c.544G>A
NM_001276695.3:c.544G>A
NM_001276696.3:c.544G>A
NM_001276697.3:c.184G>A
NM_001276698.3:c.184G>A
NM_001276699.3:c.184G>A
NM_001276760.3:c.544G>A
NM_001276761.3:c.544G>A
NP_000537.3:p.Glu221Lys
NP_000537.3:p.Glu221Lys
NP_001119584.1:p.Glu221Lys
NP_001119585.1:p.Glu221Lys
NP_001119586.1:p.Glu221Lys
NP_001119587.1:p.Glu89Lys
NP_001119588.1:p.Glu89Lys
NP_001119589.1:p.Glu89Lys
NP_001119590.1:p.Glu182Lys
NP_001263624.1:p.Glu182Lys
NP_001263625.1:p.Glu182Lys
NP_001263626.1:p.Glu62Lys
NP_001263627.1:p.Glu62Lys
NP_001263628.1:p.Glu62Lys
NP_001263689.1:p.Glu182Lys
NP_001263690.1:p.Glu182Lys
LRG_321t1:c.661G>A
LRG_321:g.17681G>A
LRG_321p1:p.Glu221Lys
NC_000017.10:g.7578188C>T
NM_000546.4:c.661G>A
NM_000546.5:c.661G>A
P04637:p.Glu221Lys
p.E221K

Protein change:

E182K

Links:

UniProtKB: P04637#VAR_045122; dbSNP: rs786201592

NCBI 1000 Genomes Browser:

rs786201592

Molecular consequence:

NM_000546.6:c.661G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.661G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.661G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.661G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.265G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.265G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.265G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.544G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.544G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.544G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.184G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.184G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.184G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.544G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.544G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Li-Fraumeni syndrome (LFS)
Synonyms:: Sarcoma family syndrome of Li and Fraumeni
Identifiers:: MONDO: MONDO:0018875; MedGen: C0085390; OMIM: PS151623

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000629849	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 13, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12826609, 29979965, 30224644, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000629849

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 13, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

Citations

PubMed

Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.

Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R, Ishioka C.

Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8424-9. Epub 2003 Jun 25.

PubMed [citation]

PMID:: 12826609
PMCID:: PMC166245

A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.

Kotler E, Shani O, Goldfeld G, Lotan-Pompan M, Tarcic O, Gershoni A, Hopf TA, Marks DS, Oren M, Segal E.

Mol Cell. 2018 Jul 5;71(1):178-190.e8. doi: 10.1016/j.molcel.2018.06.012. Erratum in: Mol Cell. 2018 Sep 6;71(5):873. doi: 10.1016/j.molcel.2018.08.013.

PubMed [citation]

PMID:: 29979965

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000629849.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 184647). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is present in population databases (rs786201592, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 221 of the TP53 protein (p.Glu221Lys).

#	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: Nov 3, 2024

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