NM_000546.6(TP53):c.871A>G (p.Lys291Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 6, 2023
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:: RCV000575139.7

Allele description [Variation Report for NM_000546.6(TP53):c.871A>G (p.Lys291Glu)]

NM_000546.6(TP53):c.871A>G (p.Lys291Glu)

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.871A>G (p.Lys291Glu)

HGVS:

NC_000017.11:g.7673749T>C
NG_017013.2:g.18802A>G
NM_000546.6:c.871A>GMANE SELECT
NM_001126112.3:c.871A>G
NM_001126113.3:c.871A>G
NM_001126114.3:c.871A>G
NM_001126115.2:c.475A>G
NM_001126116.2:c.475A>G
NM_001126117.2:c.475A>G
NM_001126118.2:c.754A>G
NM_001276695.3:c.754A>G
NM_001276696.3:c.754A>G
NM_001276697.3:c.394A>G
NM_001276698.3:c.394A>G
NM_001276699.3:c.394A>G
NM_001276760.3:c.754A>G
NM_001276761.3:c.754A>G
NP_000537.3:p.Lys291Glu
NP_000537.3:p.Lys291Glu
NP_001119584.1:p.Lys291Glu
NP_001119585.1:p.Lys291Glu
NP_001119586.1:p.Lys291Glu
NP_001119587.1:p.Lys159Glu
NP_001119588.1:p.Lys159Glu
NP_001119589.1:p.Lys159Glu
NP_001119590.1:p.Lys252Glu
NP_001263624.1:p.Lys252Glu
NP_001263625.1:p.Lys252Glu
NP_001263626.1:p.Lys132Glu
NP_001263627.1:p.Lys132Glu
NP_001263628.1:p.Lys132Glu
NP_001263689.1:p.Lys252Glu
NP_001263690.1:p.Lys252Glu
LRG_321t1:c.871A>G
LRG_321:g.18802A>G
LRG_321p1:p.Lys291Glu
NC_000017.10:g.7577067T>C
NM_000546.4:c.871A>G
NM_000546.5:c.871A>G

Protein change:

K132E

Links:

dbSNP: rs1555525126

NCBI 1000 Genomes Browser:

rs1555525126

Molecular consequence:

NM_000546.6:c.871A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.871A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.871A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.871A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.475A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.394A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.394A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.394A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.754A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; 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
SCV000664928	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 6, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12826609, 29979965, 30224644 Citation Link,
SCV002581987	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 18, 2022)	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

SCV000664928

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 6, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV002581987

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 18, 2022)

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	no	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

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 Ambry Genetics, SCV000664928.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.K291E variant (also known as c.871A>G), located in coding exon 7 of the TP53 gene, results from an A to G substitution at nucleotide position 871. The lysine at codon 291 is replaced by glutamic acid, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein, was not found to have an effect on transactivation capacity, but is predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). In addition, this variant was shown to induce apoptosis at rates higher than wild-type, however there was no evidence that this alteration had an effect on the protein's ability to transactivate TP53 target genes (Kakudo Y et al. Cancer Res. 2005 Mar 15;65(6):2108-14). Studies conducted in human cell lines indicate this alteration is proficient 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). This amino acid position is well conserved in available vertebrate species; however, glutamic acid is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Genome-Nilou Lab, SCV002581987.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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