NM_000546.6(TP53):c.473G>A (p.Arg158His) AND Li-Fraumeni syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 19, 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:: RCV000227859.27

Allele description

NM_000546.6(TP53):c.473G>A (p.Arg158His)

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.473G>A (p.Arg158His)

HGVS:

NC_000017.11:g.7675139C>T
NG_017013.2:g.17412G>A
NM_000546.6:c.473G>AMANE SELECT
NM_001126112.3:c.473G>A
NM_001126113.3:c.473G>A
NM_001126114.3:c.473G>A
NM_001126115.2:c.77G>A
NM_001126116.2:c.77G>A
NM_001126117.2:c.77G>A
NM_001126118.2:c.356G>A
NM_001276695.3:c.356G>A
NM_001276696.3:c.356G>A
NM_001276697.3:c.-5G>A
NM_001276698.3:c.-5G>A
NM_001276699.3:c.-5G>A
NM_001276760.3:c.356G>A
NM_001276761.3:c.356G>A
NP_000537.3:p.Arg158His
NP_000537.3:p.Arg158His
NP_001119584.1:p.Arg158His
NP_001119584.1:p.Arg158His
NP_001119585.1:p.Arg158His
NP_001119586.1:p.Arg158His
NP_001119587.1:p.Arg26His
NP_001119588.1:p.Arg26His
NP_001119589.1:p.Arg26His
NP_001119590.1:p.Arg119His
NP_001263624.1:p.Arg119His
NP_001263625.1:p.Arg119His
NP_001263689.1:p.Arg119His
NP_001263690.1:p.Arg119His
LRG_321t1:c.473G>A
LRG_321t2:c.473G>A
LRG_321:g.17412G>A
LRG_321:p.Arg158His
LRG_321p1:p.Arg158His
NC_000017.10:g.7578457C>T
NM_000546.4:c.473G>A
NM_000546.5:c.473G>A
NM_001126112.2:c.473G>A
P04637:p.Arg158His
p.R158H

Protein change:

R119H

Links:

UniProtKB: P04637#VAR_005907; dbSNP: rs587782144

NCBI 1000 Genomes Browser:

rs587782144

Molecular consequence:

NM_001276697.3:c.-5G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276698.3:c.-5G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001276699.3:c.-5G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000546.6:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.77G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.77G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.77G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.356G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.356G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.356G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.356G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.356G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Li-Fraumeni syndrome (LFS)
Synonyms:: Sarcoma family syndrome of Li and Fraumeni
Identifiers:: MONDO: MONDO:0018875; MedGen: C0085390; OMIM: PS151623

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000285199	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2024)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 10486318, 17606709, 18685109, 20455025, 20522432, 21601526, 23175693, 23894400, 24764719, 26014290, 29979965, 30224644, 10229196, 12826609, 21343334, 25584008, 28492532
SCV000713289	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Feb 13, 2020)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 21601526, 28349240, 23175693, 26014290, 21343334, 17308077, 10486318, 20522432, 25741868, 25584008, 24764719, 27328919, 24033266
SCV001360868	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 6, 2022)	germline	clinical testing	PubMed (22) [See all records that cite these PMIDs] 17606709, 21343334, 20407015, 25584008, 18511570, 26230955, 21519010, 27463065, 25952993, 22186996, 27680515, 27959731, 16818505, 27895058, 30327374, 11782540, 23246812, 22915647, 26585234, 27276561, 21464421, 10486318 Citation Link,
SCV001434921	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 13, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004046280	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome.

Shlien A, Tabori U, Marshall CR, Pienkowska M, Feuk L, Novokmet A, Nanda S, Druker H, Scherer SW, Malkin D.

Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11264-9. doi: 10.1073/pnas.0802970105. Epub 2008 Aug 6.

PubMed [citation]

PMID:: 18685109
PMCID:: PMC2516272

Survey of familial glioma and role of germline p16INK4A/p14ARF and p53 mutation.

Robertson LB, Armstrong GN, Olver BD, Lloyd AL, Shete S, Lau C, Claus EB, Barnholtz-Sloan J, Lai R, Il'yasova D, Schildkraut J, Bernstein JL, Olson SH, Jenkins RB, Yang P, Rynearson AL, Wrensch M, McCoy L, Wienkce JK, McCarthy B, Davis F, Vick NA, et al.

Fam Cancer. 2010 Sep;9(3):413-21. doi: 10.1007/s10689-010-9346-5. Erratum in: Fam Cancer. 2010 Sep;9(3):423-4. Rynerason, Amanda L [corrected to Rynearson, Amanda Lynn].

PubMed [citation]

PMID:: 20455025
PMCID:: PMC2922430

See all PubMed Citations (40)

Details of each submission

From Invitae, SCV000285199.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). This variant is present in population databases (rs587782144, gnomAD 0.01%). This missense change has been observed in individuals with TP53-related cancers (PMID: 10486318, 17606709, 18685109, 20455025, 20522432, 21601526, 23175693, 23894400, 24764719, 26014290). It has also been observed to segregate with disease in related individuals. This variant is also known as c.12407G>A. ClinVar contains an entry for this variant (Variation ID: 141963). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 10229196, 12826609, 21343334, 25584008). For these reasons, this variant has been classified as 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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000713289.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (13)

Description

proposed classification - variant undergoing re-assessment, contact laboratory

#	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		1	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360868.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (22)

Description

Variant summary: TP53 c.473G>A (p.Arg158His) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251268 control chromosomes.c.473G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (LFS) or LFS spectrum tumors (e.g. Varley_1999, Bougeard_2008, Ceelen_2011); and at least one of these reports described co-segregation of the variant with Li-Fraumeni Syndrome in one family (Ceelen_2011). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function and demonstrated reduced overall transcription activity (TA) on several different promoters (e.g. Monti_2011, Wasserman_2015). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Several different missense changes involving this codon (p.Arg158Leu, p.Arg158Gly, p.Arg158Cys, Arg158Pro) have been reported in individuals with TP53-related conditions (HGMD), indicating that this amino acid is important for TP53 function. Based on the evidence outlined above, the variant was classified as 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

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV001434921.1

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

Description

The c.473G>A (p.Arg158His) variant in the TP53 gene has been reported in mulitple patients/families with cancers (PMID 10486318, 17308077, 20522432, 21552135, 21761402, 23175693, 23894400 and 24764719). This variant is observed with a low minor allele frequency in the gnomAD database (1/246110). This variant is at a mutation hotspot of the DNA binding domain where other pathogenic variants in the nearby region have been reported. Functional studies demonstrated decrease P53 functionality (PMID 17606709, 21343334 and 28472496). Therefore, the c.473G>A (p.Arg158His) variant in the TP53 gene is classified as 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

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046280.1

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

Description

This variant has been previously reported as a heterozygous change in patients with TP53-related cancers and Li-Fraumeni syndrome (PMID: 10486318, 23894400, 20455025, 24764719, 26014290, 23175693, 20522432, 17606709, 21601526, 18685109). Experimental studies have shown that this variant affects TP53 function (PMID: 10229196, 12826609, 25584008, 21343334). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (1/251268) and thus is presumed to be rare. The c.473G>A (p.Arg158His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.473G>A (p.Arg158His) variant is classified as Pathogenic.

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

Last Updated: Sep 16, 2024

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