NM_000546.6(TP53):c.349G>A (p.Gly117Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 18, 2022
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:: RCV000565337.4

Allele description [Variation Report for NM_000546.6(TP53):c.349G>A (p.Gly117Arg)]

NM_000546.6(TP53):c.349G>A (p.Gly117Arg)

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.349G>A (p.Gly117Arg)

HGVS:

NC_000017.11:g.7676020C>T
NG_017013.2:g.16531G>A
NM_000546.6:c.349G>AMANE SELECT
NM_001126112.3:c.349G>A
NM_001126113.3:c.349G>A
NM_001126114.3:c.349G>A
NM_001126118.2:c.232G>A
NM_001276695.3:c.232G>A
NM_001276696.3:c.232G>A
NM_001276760.3:c.232G>A
NM_001276761.3:c.232G>A
NP_000537.3:p.Gly117Arg
NP_001119584.1:p.Gly117Arg
NP_001119585.1:p.Gly117Arg
NP_001119586.1:p.Gly117Arg
NP_001119590.1:p.Gly78Arg
NP_001263624.1:p.Gly78Arg
NP_001263625.1:p.Gly78Arg
NP_001263689.1:p.Gly78Arg
NP_001263690.1:p.Gly78Arg
LRG_321:g.16531G>A
NC_000017.10:g.7579338C>T
NM_000546.4:c.349G>A

Protein change:

G117R

Links:

dbSNP: rs1555526518

NCBI 1000 Genomes Browser:

rs1555526518

Molecular consequence:

NM_000546.6:c.349G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.349G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.349G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.349G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.232G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.232G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.232G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.232G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.232G>A - 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
SCV000664431	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 30, 2016)	germline	clinical testing	Citation Link,
SCV004360012	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 18, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29979965, 30224644, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000664431

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 30, 2016)

germline

clinical testing

Citation Link,

SCV004360012

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 18, 2022)

germline

clinical testing

PubMed (3)
[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

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

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000664431.5

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

Description

The p.G117R variant (also known as c.349G>A), located in coding exon 3 of the TP53 gene, results from a G to A substitution at nucleotide position 349. The glycine at codon 117 is replaced by arginine, an amino acid with dissimilar properties. This alteration is located in the DNA binding domain and shows a partial decrease in transactivation activity compared to wild type (IARC database: Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice acceptor site; however, direct evidence is unavailable. In addition, this amino acid position is well conserved in available vertebrate species and is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. 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 Color Diagnostics, LLC DBA Color Health, SCV004360012.1

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

Description

This missense variant replaces glycine with arginine at codon 117 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein is functional and did not exhibited a dominant-negative effect in human cell growth suppression assays (PMID: 30224644), is partially functional in yeast transactivation assays (IARC database; PMID: 12826609), and is non-functional in a human cell proliferation assay (PMID: 29979965). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 1, 2024

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