NM_000546.6(TP53):c.374C>G (p.Thr125Arg) AND Li-Fraumeni syndrome 1

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Feb 13, 2024
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:: RCV002289540.6

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:: Li-Fraumeni syndrome 1 (LFS)
Identifiers:: Gene: 553989; MedGen: C1835398; Orphanet: 524; OMIM: 151623

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002583068	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]
SCV004011719	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 10, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004931104	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Feb 13, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002583068

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]

SCV004011719

KCCC/NGS Laboratory, Kuwait Cancer Control Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 10, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004931104

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Likely pathogenic
(Feb 13, 2024)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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	unknown	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

Details of each submission

From Genome-Nilou Lab, SCV002583068.1

#	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

From KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV004011719.1

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

Description

The p.T125R variant (also known as c.374C>G) is located in coding exon 4 of the TP53 gene (NM_000546.5). This alteration 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 variant was reported in individuals with Li Fraumeni syndrome in the UK (PMID:16508005‚ 20127978‚ 20407015). This variant submitted to ClinVar database (ID;376667) by five clinical laboratory and classified as Likely pathogenic/pathogenic .This amino acid position is highly conserved (PhyloP=7.8). Functional tests done for this variant confirm the pathogenicity (PMID: 30224644, 8023157, 12826609). In addition, this alteration is predicted to be deleterious by in silico analysis (as SIFT, CADD, M-CAP, Mutation taster and PolyPhen) . Based on these evidences this variant classified as pathogenic.

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

From Myriad Genetics, Inc., SCV004931104.1

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

Description

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29979965].

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

Last Updated: Jul 15, 2024

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