NM_000546.6(TP53):c.14A>G (p.Gln5Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: May 12, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000220312.13

Allele description [Variation Report for NM_000546.6(TP53):c.14A>G (p.Gln5Arg)]

NM_000546.6(TP53):c.14A>G (p.Gln5Arg)

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.14A>G (p.Gln5Arg)

HGVS:

NC_000017.11:g.7676581T>C
NG_017013.2:g.15970A>G
NM_000546.6:c.14A>GMANE SELECT
NM_001126112.3:c.14A>G
NM_001126113.3:c.14A>G
NM_001126114.3:c.14A>G
NM_001126118.2:c.-221A>G
NM_001276695.3:c.-104A>G
NM_001276696.3:c.-104A>G
NM_001276760.3:c.-104A>G
NM_001276761.3:c.-104A>G
NP_000537.3:p.Gln5Arg
NP_000537.3:p.Gln5Arg
NP_001119584.1:p.Gln5Arg
NP_001119585.1:p.Gln5Arg
NP_001119586.1:p.Gln5Arg
LRG_321t1:c.14A>G
LRG_321:g.15970A>G
LRG_321p1:p.Gln5Arg
NC_000017.10:g.7579899T>C
NM_000546.4:c.14A>G
NM_000546.5:c.14A>G

Protein change:

Q5R

Links:

dbSNP: rs781595324

NCBI 1000 Genomes Browser:

rs781595324

Molecular consequence:

NM_001126118.2:c.-221A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276695.3:c.-104A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276696.3:c.-104A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276760.3:c.-104A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276761.3:c.-104A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.14A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.14A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.14A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.14A>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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GEO Profiles
Taxonomy Links for Protein (Select 2462497060) (1)
Taxonomy
MULTISPECIES: putative hydro-lyase [Limnospira]
MULTISPECIES: putative hydro-lyase [Limnospira]
gi|1383487528|ref|WP_108615251.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000277587	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Mar 16, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12826609, 30224644 Citation Link,
SCV000691582	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 12, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12826609, 30224644, 25741868
SCV002582187	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

SCV000277587

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Mar 16, 2021)

germline

clinical testing

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

Citation Link,

SCV000691582

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 12, 2023)

germline

clinical testing

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

SCV002582187

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	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

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, SCV000277587.7

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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, SCV000691582.5

#	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 glutamine with arginine at codon 5 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant does not adversely impact TP53 protein function (PMID: PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250676 chromosomes 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

From Genome-Nilou Lab, SCV002582187.1

#	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: May 7, 2024

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