NM_000546.6(TP53):c.1039G>A (p.Ala347Thr) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 29, 2024
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:: RCV001017117.3

Allele description [Variation Report for NM_000546.6(TP53):c.1039G>A (p.Ala347Thr)]

NM_000546.6(TP53):c.1039G>A (p.Ala347Thr)

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.1039G>A (p.Ala347Thr)

HGVS:

NC_000017.11:g.7670670C>T
NG_017013.2:g.21881G>A
NM_000546.6:c.1039G>AMANE SELECT
NM_001126112.3:c.1039G>A
NM_001126113.3:c.*58G>A
NM_001126114.3:c.*146G>A
NM_001126115.2:c.643G>A
NM_001126116.2:c.*146G>A
NM_001126117.2:c.*58G>A
NM_001126118.2:c.922G>A
NM_001276695.3:c.*58G>A
NM_001276696.3:c.*146G>A
NM_001276697.3:c.562G>A
NM_001276698.3:c.*146G>A
NM_001276699.3:c.*58G>A
NM_001276760.3:c.922G>A
NM_001276761.3:c.922G>A
NP_000537.3:p.Ala347Thr
NP_000537.3:p.Ala347Thr
NP_001119584.1:p.Ala347Thr
NP_001119587.1:p.Ala215Thr
NP_001119590.1:p.Ala308Thr
NP_001263626.1:p.Ala188Thr
NP_001263689.1:p.Ala308Thr
NP_001263690.1:p.Ala308Thr
LRG_321t1:c.1039G>A
LRG_321:g.21881G>A
LRG_321p1:p.Ala347Thr
NC_000017.10:g.7573988C>T
NM_000546.4:c.1039G>A
NM_000546.5:c.1039G>A

Protein change:

A188T

Links:

dbSNP: rs1597349147

NCBI 1000 Genomes Browser:

rs1597349147

Molecular consequence:

NM_001126113.3:c.*58G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126114.3:c.*146G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126116.2:c.*146G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001126117.2:c.*58G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276695.3:c.*58G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276696.3:c.*146G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276698.3:c.*146G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276699.3:c.*58G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000546.6:c.1039G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.1039G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.643G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.922G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.562G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.922G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.922G>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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001178147	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Feb 29, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12826609, 16007150, 20978130, 28975465, 29522266, 30224644 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001178147

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Feb 29, 2024)

germline

clinical testing

PubMed (6)
[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

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

The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library.

Kawaguchi T, Kato S, Otsuka K, Watanabe G, Kumabe T, Tominaga T, Yoshimoto T, Ishioka C.

Oncogene. 2005 Oct 20;24(46):6976-81.

PubMed [citation]

PMID:: 16007150

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV001178147.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.A347T variant (also known as c.1039G>A), located in coding exon 9 of the TP53 gene, results from a G to A substitution at nucleotide position 1039. The alanine at codon 347 is replaced by threonine, an amino acid with similar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with Li Fraumeni syndrome (LFS) (Ambry internal data). This variant has been reported in multiple individuals diagnosed with breast cancer (Siraj AK et al. Hum. Genet. 2017 11;136:1431-1444; Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This variant is in the tetramerization domain of the TP53 protein and was not able to form tetramers and had impaired transactivation capacity in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Kawaguchi T et al. Oncogene. 2005 Oct;24:6976-81; Kamada R et al. J. Biol. Chem. 2011 Jan;286:252-8). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine