NM_000546.6(TP53):c.638G>A (p.Arg213Gln) AND Li-Fraumeni syndrome 1

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jul 26, 2023
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:: RCV000144664.10

Allele description [Variation Report for NM_000546.6(TP53):c.638G>A (p.Arg213Gln)]

NM_000546.6(TP53):c.638G>A (p.Arg213Gln)

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.638G>A (p.Arg213Gln)

HGVS:

NC_000017.11:g.7674893C>T
NG_017013.2:g.17658G>A
NM_000546.6:c.638G>AMANE SELECT
NM_001126112.3:c.638G>A
NM_001126113.3:c.638G>A
NM_001126114.3:c.638G>A
NM_001126115.2:c.242G>A
NM_001126116.2:c.242G>A
NM_001126117.2:c.242G>A
NM_001126118.2:c.521G>A
NM_001276695.3:c.521G>A
NM_001276696.3:c.521G>A
NM_001276697.3:c.161G>A
NM_001276698.3:c.161G>A
NM_001276699.3:c.161G>A
NM_001276760.3:c.521G>A
NM_001276761.3:c.521G>A
NP_000537.3:p.Arg213Gln
NP_000537.3:p.Arg213Gln
NP_001119584.1:p.Arg213Gln
NP_001119585.1:p.Arg213Gln
NP_001119586.1:p.Arg213Gln
NP_001119587.1:p.Arg81Gln
NP_001119588.1:p.Arg81Gln
NP_001119589.1:p.Arg81Gln
NP_001119590.1:p.Arg174Gln
NP_001263624.1:p.Arg174Gln
NP_001263625.1:p.Arg174Gln
NP_001263626.1:p.Arg54Gln
NP_001263627.1:p.Arg54Gln
NP_001263628.1:p.Arg54Gln
NP_001263689.1:p.Arg174Gln
NP_001263690.1:p.Arg174Gln
LRG_321t1:c.638G>A
LRG_321:g.17658G>A
LRG_321p1:p.Arg213Gln
NC_000017.10:g.7578211C>T
NM_000546.4:c.638G>A
NM_000546.5:c.638G>A
P04637:p.Arg213Gln
p.R213Q

Protein change:

R174Q

Links:

UniProtKB: P04637#VAR_005955; dbSNP: rs587778720

NCBI 1000 Genomes Browser:

rs587778720

Molecular consequence:

NM_000546.6:c.638G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126112.3:c.638G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126113.3:c.638G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126114.3:c.638G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126115.2:c.242G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126116.2:c.242G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126117.2:c.242G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126118.2:c.521G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276695.3:c.521G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276696.3:c.521G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276697.3:c.161G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276698.3:c.161G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276699.3:c.161G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276760.3:c.521G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001276761.3:c.521G>A - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000189995	Pathway Genomics	no assertion criteria provided	Pathogenic (Jul 24, 2014)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21626334, 17606709, 18208484
SCV002583142	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]
SCV003843119	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Pathogenic (Oct 17, 2022)	germline	clinical testing	Citation Link,
SCV003925607	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 26, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005329582	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 20, 2023)	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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	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

Pleomorphic carcinoma of the lung arising in a patient with Li-Fraumeni syndrome: report of a case.

Kato T, Ishikawa K, Satoh M, Kondo S, Kaji M.

Surg Today. 2011 Jun;41(6):841-5. doi: 10.1007/s00595-010-4359-0. Epub 2011 May 28.

PubMed [citation]

PMID:: 21626334

Transcriptional functionality of germ line p53 mutants influences cancer phenotype.

Monti P, Ciribilli Y, Jordan J, Menichini P, Umbach DM, Resnick MA, Luzzatto L, Inga A, Fronza G.

Clin Cancer Res. 2007 Jul 1;13(13):3789-95.

PubMed [citation]

PMID:: 17606709
PMCID:: PMC2128783

See all PubMed Citations (4)

Details of each submission

From Pathway Genomics, SCV000189995.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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 Genome-Nilou Lab, SCV002583142.1

#	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 St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV003843119.1

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

Description

The TP53 c.638G>A (p.Arg213Gln) missense change has a maximum subpopulation frequency of 0.0046% in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This variant has been reported in multiple individuals with Li-Fraumeni syndrome (LFS) or LFS-associated cancers and has been found to segregate with disease in families (PMID: 16494995, 16736287, 17541742, 18208484, 19468865, 20522432, 25293557, 28369373). Computational evidence supports a deleterious effect of this variant on protein function (Align GVGD = C35, BayesDel = 0.5033). Transactivation assays show a low functioning allele according to Kato et al., and evidence of loss of function and a dominant negative effect according to Giacomelli et al. (PMID 12826609, 30224644). This variant is a somatic hotspot variant in tumors according to the Cancer Hotspots database (cancerhotspots.org). In summary, this variant meets criteria to be 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 Institute of Human Genetics, University of Leipzig Medical Center, SCV003925607.2

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

Description

Criteria applied: PS3,PS4,PM5_STR,PM2_SUP

#	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		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV005329582.1

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

Description

The observed missense variant c.638G>A (p.Arg213Gln) in the TP53 gene has been reported previously in mulitple individual(s) with Li-Fraumeni syndrome (LFS) or LFS-associated malignancies. Experimental studies have shown that this missense change affects TP53 function (Silva AG, et al., 2012; Monti P, et al., 2007). Different amino acid changes such as p.Arg213Pro and p.Arg213Leu have been reported previously as pathogenic and likely pathogenic at the same position (Dockhorn-Dworniczak B, et al., 1996; Veldore VH, et al., 2015). This variant is reported with the allele frequency 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic by multiple submitters. The amino acid Arginine at position 213 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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