NM_000546.6(TP53):c.374C>G (p.Thr125Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 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:: RCV000492090.5

Allele description [Variation Report for NM_000546.6(TP53):c.374C>G (p.Thr125Arg)]

NM_000546.6(TP53):c.374C>G (p.Thr125Arg)

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.374C>G (p.Thr125Arg)

HGVS:

NC_000017.11:g.7675995G>C
NG_017013.2:g.16556C>G
NM_000546.6:c.374C>GMANE SELECT
NM_001126112.3:c.374C>G
NM_001126113.3:c.374C>G
NM_001126114.3:c.374C>G
NM_001126118.2:c.257C>G
NM_001276695.3:c.257C>G
NM_001276696.3:c.257C>G
NM_001276760.3:c.257C>G
NM_001276761.3:c.257C>G
NP_000537.3:p.Thr125Arg
NP_000537.3:p.Thr125Arg
NP_001119584.1:p.Thr125Arg
NP_001119585.1:p.Thr125Arg
NP_001119586.1:p.Thr125Arg
NP_001119590.1:p.Thr86Arg
NP_001263624.1:p.Thr86Arg
NP_001263625.1:p.Thr86Arg
NP_001263689.1:p.Thr86Arg
NP_001263690.1:p.Thr86Arg
LRG_321t1:c.374C>G
LRG_321:g.16556C>G
LRG_321p1:p.Thr125Arg
NC_000017.10:g.7579313G>C
NM_000546.4:c.374C>G
NM_000546.5:c.374C>G

Protein change:

T125R

Links:

dbSNP: rs786201057

NCBI 1000 Genomes Browser:

rs786201057

Molecular consequence:

NM_000546.6:c.374C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.374C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.374C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.374C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.257C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.257C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.257C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.257C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.257C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000581128	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (Nov 17, 2020)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16508005, 20127978, 20407015, 29752822, 29753700 Citation Link,
SCV002582406	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (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

SCV000581128

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(Nov 17, 2020)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV002582406

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(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	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

The biological impact of the human master regulator p53 can be altered by mutations that change the spectrum and expression of its target genes.

Menendez D, Inga A, Resnick MA.

Mol Cell Biol. 2006 Mar;26(6):2297-308.

PubMed [citation]

PMID:: 16508005
PMCID:: PMC1430278

Genetic diagnosis of familial breast cancer using clonal sequencing.

Morgan JE, Carr IM, Sheridan E, Chu CE, Hayward B, Camm N, Lindsay HA, Mattocks CJ, Markham AF, Bonthron DT, Taylor GR.

Hum Mutat. 2010 Apr;31(4):484-91. doi: 10.1002/humu.21216.

PubMed [citation]

PMID:: 20127978

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000581128.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

The p.T125R pathogenic mutation (also known as c.374C>G), located in coding exon 3 of the TP53 gene, results from a C to G substitution at nucleotide position 374. The threonine at codon 125 is replaced by arginine, an amino acid with similar properties. This mutation has been reported in several families meeting clinical criteria for Li Fraumeni syndrome (Morgan J et al Hum Mutat. 2010 Apr;31(4):484-91; Waszak SM et al. Lancet Oncol. 2018 06;19:785-798; Li JY et al. Int J Cancer. 2019 01;144:281-289). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a 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). Other studies in mammalian cells showed that this alteration has decreased sensitivity to radiation, decreased suppression of colony growth, and reduced induction of apoptosis compared to wild type (Menendez D et al. Mol. Cell. Biol. 2006 Mar;26:2297-308). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002582406.1

#	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: Apr 15, 2024

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