NM_000546.6(TP53):c.358A>G (p.Lys120Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 2, 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:: RCV000129457.7

Allele description [Variation Report for NM_000546.6(TP53):c.358A>G (p.Lys120Glu)]

NM_000546.6(TP53):c.358A>G (p.Lys120Glu)

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.358A>G (p.Lys120Glu)

Other names:

p.K120E:AAG>GAG

HGVS:

NC_000017.11:g.7676011T>C
NG_017013.2:g.16540A>G
NM_000546.6:c.358A>GMANE SELECT
NM_001126112.3:c.358A>G
NM_001126113.3:c.358A>G
NM_001126114.3:c.358A>G
NM_001126118.2:c.241A>G
NM_001276695.3:c.241A>G
NM_001276696.3:c.241A>G
NM_001276760.3:c.241A>G
NM_001276761.3:c.241A>G
NP_000537.3:p.Lys120Glu
NP_000537.3:p.Lys120Glu
NP_001119584.1:p.Lys120Glu
NP_001119585.1:p.Lys120Glu
NP_001119586.1:p.Lys120Glu
NP_001119590.1:p.Lys81Glu
NP_001263624.1:p.Lys81Glu
NP_001263625.1:p.Lys81Glu
NP_001263689.1:p.Lys81Glu
NP_001263690.1:p.Lys81Glu
LRG_321t1:c.358A>G
LRG_321:g.16540A>G
LRG_321p1:p.Lys120Glu
NC_000017.10:g.7579329T>C
NM_000546.4:c.358A>G
NM_000546.5:c.358A>G
P04637:p.Lys120Glu
p.K120E

Protein change:

K120E

Links:

UniProtKB: P04637#VAR_044699; dbSNP: rs121912658

NCBI 1000 Genomes Browser:

rs121912658

Molecular consequence:

NM_000546.6:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.358A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.241A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.241A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.241A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.241A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.241A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Hereditary neoplastic syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000184227	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29979965, 30224644 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184227

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 2, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

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

Mutational processes shape the landscape of TP53 mutations in human cancer.

Giacomelli AO, Yang X, Lintner RE, McFarland JM, Duby M, Kim J, Howard TP, Takeda DY, Ly SH, Kim E, Gannon HS, Hurhula B, Sharpe T, Goodale A, Fritchman B, Steelman S, Vazquez F, Tsherniak A, Aguirre AJ, Doench JG, Piccioni F, Roberts CWM, et al.

Nat Genet. 2018 Oct;50(10):1381-1387. doi: 10.1038/s41588-018-0204-y. Epub 2018 Sep 17.

PubMed [citation]

PMID:: 30224644
PMCID:: PMC6168352

Details of each submission

From Ambry Genetics, SCV000184227.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.K120E pathogenic mutation (also known as c.358A>G), located in coding exon 3 of the TP53 gene, results from an A to G substitution at nucleotide position 358. The lysine at codon 120 is replaced by glutamic acid, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has no dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Internal structural analysis shows K120E is located in the same groove as several other known likely pathogenic variants and perturbs the structure with equivalent energies and greater energies (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: May 16, 2025

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