NM_000546.6(TP53):c.772G>A (p.Glu258Lys) AND Li-Fraumeni syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 18, 2024
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:: RCV000792895.10

Allele description [Variation Report for NM_000546.6(TP53):c.772G>A (p.Glu258Lys)]

NM_000546.6(TP53):c.772G>A (p.Glu258Lys)

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.772G>A (p.Glu258Lys)

Other names:

p.E258K:GAA>AAA

HGVS:

NC_000017.11:g.7674191C>T
NG_017013.2:g.18360G>A
NM_000546.6:c.772G>AMANE SELECT
NM_001126112.3:c.772G>A
NM_001126113.3:c.772G>A
NM_001126114.3:c.772G>A
NM_001126115.2:c.376G>A
NM_001126116.2:c.376G>A
NM_001126117.2:c.376G>A
NM_001126118.2:c.655G>A
NM_001276695.3:c.655G>A
NM_001276696.3:c.655G>A
NM_001276697.3:c.295G>A
NM_001276698.3:c.295G>A
NM_001276699.3:c.295G>A
NM_001276760.3:c.655G>A
NM_001276761.3:c.655G>A
NP_000537.3:p.Glu258Lys
NP_000537.3:p.Glu258Lys
NP_001119584.1:p.Glu258Lys
NP_001119585.1:p.Glu258Lys
NP_001119586.1:p.Glu258Lys
NP_001119587.1:p.Glu126Lys
NP_001119588.1:p.Glu126Lys
NP_001119589.1:p.Glu126Lys
NP_001119590.1:p.Glu219Lys
NP_001263624.1:p.Glu219Lys
NP_001263625.1:p.Glu219Lys
NP_001263626.1:p.Glu99Lys
NP_001263627.1:p.Glu99Lys
NP_001263628.1:p.Glu99Lys
NP_001263689.1:p.Glu219Lys
NP_001263690.1:p.Glu219Lys
LRG_321t1:c.772G>A
LRG_321:g.18360G>A
LRG_321p1:p.Glu258Lys
NC_000017.10:g.7577509C>T
NM_000546.4:c.772G>A
NM_000546.5:c.772G>A
P04637:p.Glu258Lys

Protein change:

E126K; GLU258LYS

Links:

UniProtKB: P04637#VAR_005991; OMIM: 191170.0002; dbSNP: rs121912652

NCBI 1000 Genomes Browser:

rs121912652

Molecular consequence:

NM_000546.6:c.772G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.772G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.772G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.772G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.376G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.376G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.376G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.655G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.655G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.655G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.295G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.295G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.295G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.655G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.655G>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
SCV000932221	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 18, 2024)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 1978757, 9667734, 10922393, 17606709, 21552135, 29625052, 34529667, 12826609, 20128691, 21343334, 29979965, 30224644, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000932221

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 18, 2024)

germline

clinical testing

PubMed (13)
[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

Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.

Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, et al.

Science. 1990 Nov 30;250(4985):1233-8. Erratum in: Science. 1993 Feb 12;259(5097):878..

PubMed [citation]

PMID:: 1978757

Comprehensive mutational scanning of the p53 coding region by two-dimensional gene scanning.

Rines RD, van Orsouw NJ, Sigalas I, Li FP, Eng C, Vijg J.

Carcinogenesis. 1998 Jun;19(6):979-84.

PubMed [citation]

PMID:: 9667734

See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000932221.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 258 of the TP53 protein (p.Glu258Lys). This variant is present in population databases (rs121912652, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 1978757, 9667734, 10922393, 17606709, 21552135, 29625052, 34529667; Invitae). ClinVar contains an entry for this variant (Variation ID: 12348). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 20128691, 21343334, 29979965, 30224644). 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: Feb 25, 2025

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