NM_000546.6(TP53):c.188C>G (p.Ala63Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 8, 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:: RCV000216082.11

Allele description [Variation Report for NM_000546.6(TP53):c.188C>G (p.Ala63Gly)]

NM_000546.6(TP53):c.188C>G (p.Ala63Gly)

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.188C>G (p.Ala63Gly)

Other names:

NM_000546.6(TP53):c.188C>G

HGVS:

NC_000017.11:g.7676181G>C
NG_017013.2:g.16370C>G
NM_000546.6:c.188C>GMANE SELECT
NM_001126112.3:c.188C>G
NM_001126113.3:c.188C>G
NM_001126114.3:c.188C>G
NM_001126118.2:c.71C>G
NM_001276695.3:c.71C>G
NM_001276696.3:c.71C>G
NM_001276760.3:c.71C>G
NM_001276761.3:c.71C>G
NP_000537.3:p.Ala63Gly
NP_000537.3:p.Ala63Gly
NP_001119584.1:p.Ala63Gly
NP_001119585.1:p.Ala63Gly
NP_001119586.1:p.Ala63Gly
NP_001119590.1:p.Ala24Gly
NP_001263624.1:p.Ala24Gly
NP_001263625.1:p.Ala24Gly
NP_001263689.1:p.Ala24Gly
NP_001263690.1:p.Ala24Gly
LRG_321t1:c.188C>G
LRG_321:g.16370C>G
LRG_321p1:p.Ala63Gly
NC_000017.10:g.7579499G>C
NM_000546.4:c.188C>G
NM_000546.5:c.188C>G

Protein change:

A24G

Links:

dbSNP: rs372201428

NCBI 1000 Genomes Browser:

rs372201428

Molecular consequence:

NM_000546.6:c.188C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.188C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.188C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.188C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.71C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.71C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.71C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.71C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.71C>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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Gene Links for GEO Profiles (Select 131517021) (1)
Gene
ASB13 ankyrin repeat and SOCS box containing 13 [Homo sapiens]
ASB13 ankyrin repeat and SOCS box containing 13 [Homo sapiens]
Gene ID:79754

Gene
Homologene neighbors for GEO Profiles (Select 131526008) (0)
GEO Profiles
Profile neighbors for GEO Profiles (Select 131517021) (199)
GEO Profiles
Chromosome neighbors for GEO Profiles (Select 131556417) (20)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000272992	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Oct 22, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12826609, 30224644 Citation Link,
SCV000908801	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 8, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11359905, 12826609, 30224644, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000272992

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Oct 22, 2020)

germline

clinical testing

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

Citation Link,

SCV000908801

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 8, 2023)

germline

clinical testing

PubMed (4)
[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

The corepressor mSin3a interacts with the proline-rich domain of p53 and protects p53 from proteasome-mediated degradation.

Zilfou JT, Hoffman WH, Sank M, George DL, Murphy M.

Mol Cell Biol. 2001 Jun;21(12):3974-85.

PubMed [citation]

PMID:: 11359905
PMCID:: PMC87060

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

See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000272992.7

#	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, SCV000908801.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant is located in the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant behaves like wild-type in yeast transactivation studies and human cell growth suppression assays (PMID: 11359905, 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has been identified in 1/31376 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

Last Updated: Nov 10, 2024

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