NM_000546.6(TP53):c.733G>T (p.Gly245Cys) AND Li-Fraumeni syndrome 1

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 16, 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:: RCV000013142.28

Allele description [Variation Report for NM_000546.6(TP53):c.733G>T (p.Gly245Cys)]

NM_000546.6(TP53):c.733G>T (p.Gly245Cys)

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.733G>T (p.Gly245Cys)

Other names:

p.G245C:GGC>TGC

HGVS:

NC_000017.11:g.7674230C>A
NG_017013.2:g.18321G>T
NM_000546.6:c.733G>TMANE SELECT
NM_001126112.3:c.733G>T
NM_001126113.3:c.733G>T
NM_001126114.3:c.733G>T
NM_001126115.2:c.337G>T
NM_001126116.2:c.337G>T
NM_001126117.2:c.337G>T
NM_001126118.2:c.616G>T
NM_001276695.3:c.616G>T
NM_001276696.3:c.616G>T
NM_001276697.3:c.256G>T
NM_001276698.3:c.256G>T
NM_001276699.3:c.256G>T
NM_001276760.3:c.616G>T
NM_001276761.3:c.616G>T
NP_000537.3:p.Gly245Cys
NP_000537.3:p.Gly245Cys
NP_001119584.1:p.Gly245Cys
NP_001119585.1:p.Gly245Cys
NP_001119586.1:p.Gly245Cys
NP_001119587.1:p.Gly113Cys
NP_001119588.1:p.Gly113Cys
NP_001119589.1:p.Gly113Cys
NP_001119590.1:p.Gly206Cys
NP_001263624.1:p.Gly206Cys
NP_001263625.1:p.Gly206Cys
NP_001263626.1:p.Gly86Cys
NP_001263627.1:p.Gly86Cys
NP_001263628.1:p.Gly86Cys
NP_001263689.1:p.Gly206Cys
NP_001263690.1:p.Gly206Cys
LRG_321t1:c.733G>T
LRG_321:g.18321G>T
LRG_321p1:p.Gly245Cys
NC_000017.10:g.7577548C>A
NM_000546.4:c.733G>T
NM_000546.5:c.733G>T
P04637:p.Gly245Cys

Protein change:

G113C; GLY245CYS

Links:

UniProtKB: P04637#VAR_005972; OMIM: 191170.0003; dbSNP: rs28934575

NCBI 1000 Genomes Browser:

rs28934575

Molecular consequence:

NM_000546.6:c.733G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.733G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.733G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.733G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.337G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.337G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.337G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.616G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.616G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.616G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.256G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.256G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.256G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.616G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.616G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Ogrq2 AND (alive[prop]) (0)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000033389	OMIM	no assertion criteria provided	Pathogenic (Jul 15, 1992)	germline	literature only	PubMed (1) [See all records that cite this PMID] Malkin, D., Li, F. P., Strong, L. C., Fraumeni, J. F., Jr., Nelson, C. E., Kim, D. H., Kassel, J., Gryka, M. A., Bischoff, F. Z., Tainsky, M. A., Friend, S. H. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250: 1233-1238, 1990. Note: Erratum: Science 259: 878 only, 1993.,
SCV002583127	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004931847	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Feb 16, 2024)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 1631137, 10629033, 29979965, 1978757, 23406775 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000033389

OMIM

no assertion criteria provided

Pathogenic
(Jul 15, 1992)

germline

literature only

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

Malkin, D., Li, F. P., Strong, L. C., Fraumeni, J. F., Jr., Nelson, C. E., Kim, D. H., Kassel, J., Gryka, M. A., Bischoff, F. Z., Tainsky, M. A., Friend, S. H. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250: 1233-1238, 1990. Note: Erratum: Science 259: 878 only, 1993.,

SCV002583127

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 18, 2022)

germline

clinical testing

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

SCV004931847

Myriad Genetics, Inc.

criteria provided, single submitter

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

Pathogenic
(Feb 16, 2024)

unknown

clinical testing

PubMed (5)
[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	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	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

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

Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein.

Frebourg T, Kassel J, Lam KT, Gryka MA, Barbier N, Andersen TI, Børresen AL, Friend SH.

Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6413-7.

PubMed [citation]

PMID:: 1631137
PMCID:: PMC49511

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000033389.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a family with the Li-Fraumeni syndrome-1 (151623), Malkin et al. (1990) identified a G-to-T mutation at the first nucleotide of codon 245, resulting in substitution of cysteine for glycine (G245C).

Frebourg et al. (1992) showed that the germline G245C mutation resulted in loss of tumor suppressor activity in malignant cells.

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

From Genome-Nilou Lab, SCV002583127.1

#	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 Myriad Genetics, Inc., SCV004931847.1

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

Description

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 1631137, 10629033, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 1978757, 23406775].

#	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: Sep 16, 2024

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