proposed classification - variant undergoing re-assessment, contact laboratory
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.638G>A (p.Arg213Gln)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic/Likely pathogenic
18 out of 26 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
26
Somatic
Clinical impact
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
2 out of 2 submissions contributed to this classification
Help
The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
2
Somatic
Oncogenicity
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
Oncogenic
This classification is based on the single submission received
Help
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
1
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.638G>A (p.Arg213Gln)
Variation ID: 135359 Accession: VCV000135359.73
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7674893 (GRCh38) [ NCBI UCSC ] 17: 7578211 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 9, 2014 May 3, 2025 Dec 18, 2024 Somatic - Clinical impact Nov 22, 2025 Nov 22, 2025 May 19, 2025 Somatic - Oncogenicity Jan 3, 2026 Jan 3, 2026 Dec 29, 2025 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.638G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg213Gln missense NM_001126112.3:c.638G>A NP_001119584.1:p.Arg213Gln missense NM_001126113.3:c.638G>A NP_001119585.1:p.Arg213Gln missense NM_001126114.3:c.638G>A NP_001119586.1:p.Arg213Gln missense NM_001126115.2:c.242G>A NP_001119587.1:p.Arg81Gln missense NM_001126116.2:c.242G>A NP_001119588.1:p.Arg81Gln missense NM_001126117.2:c.242G>A NP_001119589.1:p.Arg81Gln missense NM_001126118.2:c.521G>A NP_001119590.1:p.Arg174Gln missense NM_001276695.3:c.521G>A NP_001263624.1:p.Arg174Gln missense NM_001276696.3:c.521G>A NP_001263625.1:p.Arg174Gln missense NM_001276697.3:c.161G>A NP_001263626.1:p.Arg54Gln missense NM_001276698.3:c.161G>A NP_001263627.1:p.Arg54Gln missense NM_001276699.3:c.161G>A NP_001263628.1:p.Arg54Gln missense NM_001276760.3:c.521G>A NP_001263689.1:p.Arg174Gln missense NM_001276761.3:c.521G>A NP_001263690.1:p.Arg174Gln missense NC_000017.11:g.7674893C>T NC_000017.10:g.7578211C>T NG_017013.2:g.17658G>A LRG_321:g.17658G>A LRG_321t1:c.638G>A LRG_321p1:p.Arg213Gln P04637:p.Arg213Gln - Protein change
- R174Q, R213Q, R81Q, R54Q
- Other names
- -
- Canonical SPDI
- NC_000017.11:7674892:C:T
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3808 | 3911 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| not provided (1) |
no classification provided
|
Sep 19, 2013 | RCV000122176.5 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 18, 2024 | RCV000123099.28 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jul 26, 2023 | RCV000144664.11 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Nov 22, 2024 | RCV000130072.19 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Feb 23, 2024 | RCV000420734.16 | |
| drug response (1) |
no assertion criteria provided
|
Nov 27, 2017 | RCV000626448.4 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 30, 2019 | RCV001255672.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 9, 2019 | RCV001798386.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 22, 2023 | RCV003460862.1 | |
|
TP53-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 17, 2024 | RCV004745203.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Collapse all rows
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Jan 10, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731632.3
First in ClinVar: Apr 09, 2018 Last updated: Jul 03, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
|
|
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Pathogenic
(Feb 21, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome |
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434920.1
First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
Comment:
show
The c.638G>A (p.Arg213Gln) variant in the TP53 gene has been reported in multiple families affected with Li-Fraumeni (LFS) or Li-Fraumeni-like (LFL) syndromes (PMID 16736287, 16494995, 19468865, 20522432) and is extremely rare in general population databases. Experimental studies have shown that this missense change affects TP53 protein function (PMID 8080050, 10871862, 17606709,17311302, 21343334). This variant is located within a mutational hotspot that encodes the DNA-binding domain of the p53 protein. Arg213 is a highly conserved residue and multiple lines of algorithms predict deleterious effect of the p.Arg213Gln change. Therefore, we classify this c.638G>A (p.Arg213Gln) variant as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Mar 27, 2018)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449717.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
|
|
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Pathogenic
(Aug 09, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Breast and/or ovarian cancer |
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV002042828.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Jan 30, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003800820.2
First in ClinVar: Feb 13, 2023 Last updated: Nov 11, 2023 |
Comment:
show
Variant summary: TP53 c.638G>A (p.Arg213Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four 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 251462 control chromosomes (gnomAD). c.638G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and associated cancers, and has been shown to segregate with disease within families (e.g. Ruijs_2006, Arcand_2008, Sheng_2020). These data indicate that the variant is very likely to be associated with disease. Experimental studies have shown that this missense change significantly affects the functional activity of the TP53 protein, diminishing its DNA-binding and transcriptional transactivation activities in yeast-based assays, and has been functionally classified as a partial deficiency (PD) or severe deficiency (SD) allele (PMID: 16736287, 21343334, 12826609, 17606709). Ten ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Aug 22, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Adrenocortical carcinoma, hereditary |
Baylor Genetics
Accession: SCV004206242.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
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Likely pathogenic
(Aug 16, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome
(Autosomal dominant inheritance)
|
Molecular Diagnostics Laboratory, Catalan Institute of Oncology
Accession: SCV005407759.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
show
c.638G>A, located in exon 6 of the TP53 gene, is predicted to result in the substitution of Arginine by Glutamine at codon 213, p.(Arg213Gln). This variant is found in 1/236928 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C35; BayesDel: 0.5) (PP3). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 3 individuals affected with a TP53-related phenotype, which awards 2 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 25293557, 16736287) (PS4_moderate). It has been reported in ClinVar (13x as pathogenic, 22x as likely pathogenic, 1x NA), LOVD (3x as pathogenic, 1x as NA) and CancerHotspots (25 somatic observations, PM1). Based on the currently available information, c.638G>A is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Platform type: next-gen sequencing
|
|
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Pathogenic
(Nov 22, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Ambry Genetics
Accession: SCV000184899.10
First in ClinVar: Aug 06, 2014 Last updated: Jan 13, 2025 |
Comment:
show
The p.R213Q pathogenic mutation (also known as c.638G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 638. The arginine at codon 213 is replaced by glutamine, an amino acid with similar properties. In one study, p.R213Q was detected in a 3-month-old boy with choroid plexus carcinoma whose unaffected father was also found to carry the alteration (Becherini et al. Neuropathol. Appl. Neurobiol. 2008 Oct;34(5):564-8). Other studies have reported this alteration in individuals with clinical histories suspicious for Li-Fraumeni syndrome (LFS) (Achatz MI et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102; Arcand SL et al. Breast Cancer Res Treat. 2008 Apr;108(3):399-408; Pinto C et al. Fam. Cancer. 2009 May;8(4):383-90; Ruijs MW et al. J. Med. Genet. 2010 Jun;47(6):421-8; Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). 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; Zerdoumi Y et al. Hum. Mol. Genet., 2017 07;26:2591-2602). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been detected in multiple families satisfying clinical diagnostic criteria for LFS to date (Ambry internal data). However, it has also been detected in individuals with atypical/mild LFS phenotypes, suggesting variable expressivity and penetrance (Ambry internal data). 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 available evidence, this alteration is classified as a pathogenic mutation. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Jun 18, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Genome-Nilou Lab
Accession: SCV002582482.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
|
|
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Pathogenic
(Jun 18, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome 1 |
Genome-Nilou Lab
Accession: SCV002583142.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
|
|
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Pathogenic
(Nov 16, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000517027.7
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
Comment:
show
Published functional studies demonstrate a damaging effect: partial to non-functional transactivation activity, deficient in targeting the consensus binding sequencing of p53 in the regulatory region of the p21 gene, resulting in an inability to up-regulate cell cycle arrest and apoptosis (Pan 2000, Kato 2003, Monti 2011, Zhang 2014, Kotler 2018); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25268584, 16494995, 29979965, 28472496, 30224644, 28643165, 29058986, 25925845, 10871862, 14583457, 23259501, 16736287, 19468865, 8080050, 24728327, 1915267, 8492087, 21343334, 17606709, 24384472, 26270727, 26829319, 20522432, 28369373, 29076966, 18208484, 28861920, 29489754, 28724667, 30455982, 30675318, 30299350, 30720243, 30840781, 31119730, 30577483, 31481248, 31105275, 31447099, 33138793, 33818021, 17541742, 15510160) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
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Pathogenic
(Oct 17, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome 1 |
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV003843119.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
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Pathogenic
(Jan 22, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
|
All of Us Research Program, National Institutes of Health
Accession: SCV004823777.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
show
This missense variant replaces arginine with glutamine at codon 213 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of DNA binding and transactivation activity of TP53 protein (PMID: 7885831, 10871862, 12826609, 16736287, 24384472). This variant has been reported in an individual affected with Li-Fraumeni syndrome (Color internal data) and in individuals meeting the Chompret criteria of Li-Fraumeni syndrome (PMID: 17541742, 23259501). In a large pedigree that meets the Birch criteria of Li-Fraumeni-like syndrome, this variant has been shown to segregate with late-onset breast cancer, ovarian cancer, colorectal cancer, renal cell cancer, melanoma, mesothelioma and lung cancer in 12 family members (PMID: 16736287). This variant has been observed in individuals not meeting Li-Fraumeni syndrome diagnostic criteria but affected with breast cancer (PMID: 17541742, 20522432, 31119730, 32019277; Color internal data) and sarcoma (PMID: 19468865). An analysis of IARC's TP53 germline variant dataset has shown this variant to exhibit reduced penetrance (PMID: 29076966). This variant has been identified in 1/251462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. This variant may display reduced penetrance relative to typical pathogenic TP53 variants. Medical management should be considered based on the individual's personal and family history. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
|
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Pathogenic
(May 20, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome 1
(Autosomal dominant inheritance)
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005329582.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
show
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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Clinical Features:
Neoplasm (present)
Comment on clinical features:
Current clinical features: I/V/O multiple primary cancer(Breast,lung and uterus) Consanguinity: Absent Family history: Brother diagnosed with Ca prostate
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pathogenic
(Feb 23, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001469324.2
First in ClinVar: Jan 26, 2021 Last updated: Jan 19, 2025 |
Comment:
show
The TP53 c.638G>A (p.Arg213Gln) variant has been reported in the published literature in individuals with late onset breast, ovarian, and choroid plexus carcinomas, as well as in affected individuals with Li-Fraumeni syndrome (PMIDs: 32019277 (2020), 31119730 (2020), 30720243 (2019), 26270727 (2015), 24728327 (2014), 23259501 (2012), 16736287 (2006)). It has also been observed as early onset in an affected individual with gray zone lymphoma (PMID: 30299350 (2019)). A yeast based functional study of this variant showed a lack of transcriptional activity (PMID: 1676287 (2006)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
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Pathogenic
(Dec 18, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000166400.13
First in ClinVar: Jun 15, 2014 Last updated: Feb 25, 2025 |
Comment:
show
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 213 of the TP53 protein (p.Arg213Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Li-Fraumeni syndrome (LFS) or LFS-associated malignancies (PMID: 16494995, 16736287, 17541742, 18208484, 19468865, 20522432, 23259501). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 135359). Invitae Evidence Modeling incorporating data from in vitro 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: 12826609, 16736287, 17606709, 21343334). For these reasons, this variant has been classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jul 26, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Li-Fraumeni syndrome 1
(Autosomal dominant inheritance)
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV003925607.3
First in ClinVar: May 20, 2023 Last updated: Apr 13, 2025 |
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: yes
Clinical Features:
Tetraparesis (present) , Polyneuropathy (present)
Sex: male
|
|
|
Pathogenic
(Jun 18, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Color Diagnostics, LLC DBA Color Health
Accession: SCV000292157.4
First in ClinVar: Jul 08, 2016 Last updated: May 03, 2025 |
Comment:
show
This missense variant replaces arginine with glutamine at codon 213 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant results in the loss of DNA binding and transactivation activity of TP53 protein (PMID: 7885831, 10871862, 12826609, 16736287, 24384472). This variant has been reported in an individual affected with Li-Fraumeni syndrome (Color internal data) and in individuals meeting the Chompret criteria of Li-Fraumeni syndrome (PMID: 17541742, 23259501). In a large pedigree that meets the Birch criteria of Li-Fraumeni-like syndrome, this variant has been shown to segregate with late-onset breast cancer, ovarian cancer, colorectal cancer, renal cell cancer, melanoma, mesothelioma and lung cancer in 12 family members (PMID: 16736287). This variant has been observed in individuals not meeting Li-Fraumeni syndrome diagnostic criteria but affected with breast cancer (PMID: 17541742, 20522432, 31119730, 32019277; Color internal data) and sarcoma (PMID: 19468865). An analysis of the IARC TP53 germline variant dataset has shown this variant to exhibit reduced penetrance (PMID: 29076966). This variant has been identified in 1/251462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. This variant may display reduced penetrance relative to typical pathogenic TP53 variants. Medical management should be considered based on the individual's personal and family history. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Platform type: NGS
|
|
|
Pathogenic
(Jul 24, 2014)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Li-Fraumeni syndrome 1 |
Pathway Genomics
Accession: SCV000189995.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Aug 26, 2022)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Hereditary cancer-predisposing syndrome |
BRCAlab, Lund University
Accession: SCV002589031.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Jun 17, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
TP53-related condition
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005365967.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
show
The TP53 c.638G>A variant is predicted to result in the amino acid substitution p.Arg213Gln. This variant has been reported in individuals with Li-Fraumeni syndrome or related cancers (Ruijs et al. 2006. PubMed ID: 16736287; Table S1A, Monti et al. 2007. PubMed ID: 17606709; Arcand et al. 2008. PubMed ID: 17541742; Ruijs et al. 2010. PubMed ID: 20522432; Table S3, Sun et al. 2017. PubMed ID: 28724667; Table S3, Rana et al. 2019. PubMed ID: 31105275). Functional studies showed that this variant altered DNA-binding and transactivation activities (Table S1 and Table S3, Monti et al. 2011. PubMed ID: 21343334; Zhang et al. 2014. PubMed ID: 24384472; Zerdoumi et al. 2017. PubMed ID: 28369373). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and interpreted as pathogenic by most of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135359/). This variant is interpreted as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
drug response
(Nov 27, 2017)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
PARP Inhibitor response
Drug used for
Cancer
|
Oxford Haemato-Oncology Service, Oxford University Hospitals NHS Foundation Trust
Accession: SCV000734838.1
First in ClinVar: May 06, 2018 Last updated: May 06, 2018 |
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Test name: WGS
Platform type: Next-Generation Sequencing
Platform name: HiSeq
Method: PCR-Free library Preparation on germline and tumour. Data analyzed after Tumour-Normal Substraction.
|
|
|
Pathogenic
(Apr 30, 2019)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Lip and oral cavity carcinoma |
Institute of Medical Sciences, Banaras Hindu University
Accession: SCV001432237.1
First in ClinVar: Sep 18, 2020 Last updated: Sep 18, 2020 |
Observation: 1
Collection method: research
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: research
Allele origin: somatic
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001905965.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953963.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
not provided
(Sep 19, 2013)
N
Not contributing to aggregate classification
|
no classification provided
|
AllHighlyPenetrant |
ITMI
Accession: SCV000086391.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation:
7
Observation 1
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: Whole_cohort
Platform type: next-gen sequencing
Platform name: Complete Genomics
Observation 2
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: African
Platform type: next-gen sequencing
Platform name: Complete Genomics
Observation 3
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: African_European
Platform type: next-gen sequencing
Platform name: Complete Genomics
Observation 4
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: Central_Asian
Platform type: next-gen sequencing
Platform name: Complete Genomics
Observation 5
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: East_Asian
Platform type: next-gen sequencing
Platform name: Complete Genomics
Observation 6
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: European
Platform type: next-gen sequencing
Platform name: Complete Genomics
Observation 7
Collection method: reference population
Allele origin: germline
Affected status: unknown
Ethnicity/Population group: Hispanic
Platform Type: next-gen sequencing
Platform Name: Complete Genomics
|
|
Comment:
Comment:
The c.638G>A (p.Arg213Gln) variant in the TP53 gene has been reported in multiple families affected with Li-Fraumeni (LFS) or Li-Fraumeni-like (LFL) syndromes (PMID 16736287, 16494995, 19468865, 20522432) and is extremely rare in general population databases. Experimental studies have shown that this missense change affects TP53 protein function (PMID 8080050, 10871862, 17606709,17311302, 21343334). This variant is located within a mutational hotspot that encodes the DNA-binding domain of the p53 protein. Arg213 is a highly conserved residue and multiple lines of algorithms predict deleterious effect of the p.Arg213Gln change. Therefore, we classify this c.638G>A (p.Arg213Gln) variant as pathogenic.
Comment:
Variant summary: TP53 c.638G>A (p.Arg213Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four 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 251462 control chromosomes (gnomAD). c.638G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and associated cancers, and has been shown to segregate with disease within families (e.g. Ruijs_2006, Arcand_2008, Sheng_2020). These data indicate that the variant is very likely to be associated with disease. Experimental studies have shown that this missense change significantly affects the functional activity of the TP53 protein, diminishing its DNA-binding and transcriptional transactivation activities in yeast-based assays, and has been functionally classified as a partial deficiency (PD) or severe deficiency (SD) allele (PMID: 16736287, 21343334, 12826609, 17606709). Ten ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
c.638G>A, located in exon 6 of the TP53 gene, is predicted to result in the substitution of Arginine by Glutamine at codon 213, p.(Arg213Gln). This variant is found in 1/236928 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C35; BayesDel: 0.5) (PP3). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 3 individuals affected with a TP53-related phenotype, which awards 2 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 25293557, 16736287) (PS4_moderate). It has been reported in ClinVar (13x as pathogenic, 22x as likely pathogenic, 1x NA), LOVD (3x as pathogenic, 1x as NA) and CancerHotspots (25 somatic observations, PM1). Based on the currently available information, c.638G>A is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
Comment:
The p.R213Q pathogenic mutation (also known as c.638G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 638. The arginine at codon 213 is replaced by glutamine, an amino acid with similar properties. In one study, p.R213Q was detected in a 3-month-old boy with choroid plexus carcinoma whose unaffected father was also found to carry the alteration (Becherini et al. Neuropathol. Appl. Neurobiol. 2008 Oct;34(5):564-8). Other studies have reported this alteration in individuals with clinical histories suspicious for Li-Fraumeni syndrome (LFS) (Achatz MI et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102; Arcand SL et al. Breast Cancer Res Treat. 2008 Apr;108(3):399-408; Pinto C et al. Fam. Cancer. 2009 May;8(4):383-90; Ruijs MW et al. J. Med. Genet. 2010 Jun;47(6):421-8; Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). 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; Zerdoumi Y et al. Hum. Mol. Genet., 2017 07;26:2591-2602). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been detected in multiple families satisfying clinical diagnostic criteria for LFS to date (Ambry internal data). However, it has also been detected in individuals with atypical/mild LFS phenotypes, suggesting variable expressivity and penetrance (Ambry internal data). 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 available evidence, this alteration is classified as a pathogenic mutation.
Comment:
Published functional studies demonstrate a damaging effect: partial to non-functional transactivation activity, deficient in targeting the consensus binding sequencing of p53 in the regulatory region of the p21 gene, resulting in an inability to up-regulate cell cycle arrest and apoptosis (Pan 2000, Kato 2003, Monti 2011, Zhang 2014, Kotler 2018); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25268584, 16494995, 29979965, 28472496, 30224644, 28643165, 29058986, 25925845, 10871862, 14583457, 23259501, 16736287, 19468865, 8080050, 24728327, 1915267, 8492087, 21343334, 17606709, 24384472, 26270727, 26829319, 20522432, 28369373, 29076966, 18208484, 28861920, 29489754, 28724667, 30455982, 30675318, 30299350, 30720243, 30840781, 31119730, 30577483, 31481248, 31105275, 31447099, 33138793, 33818021, 17541742, 15510160)
Comment:
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.
Comment:
This missense variant replaces arginine with glutamine at codon 213 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of DNA binding and transactivation activity of TP53 protein (PMID: 7885831, 10871862, 12826609, 16736287, 24384472). This variant has been reported in an individual affected with Li-Fraumeni syndrome (Color internal data) and in individuals meeting the Chompret criteria of Li-Fraumeni syndrome (PMID: 17541742, 23259501). In a large pedigree that meets the Birch criteria of Li-Fraumeni-like syndrome, this variant has been shown to segregate with late-onset breast cancer, ovarian cancer, colorectal cancer, renal cell cancer, melanoma, mesothelioma and lung cancer in 12 family members (PMID: 16736287). This variant has been observed in individuals not meeting Li-Fraumeni syndrome diagnostic criteria but affected with breast cancer (PMID: 17541742, 20522432, 31119730, 32019277; Color internal data) and sarcoma (PMID: 19468865). An analysis of IARC's TP53 germline variant dataset has shown this variant to exhibit reduced penetrance (PMID: 29076966). This variant has been identified in 1/251462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. This variant may display reduced penetrance relative to typical pathogenic TP53 variants. Medical management should be considered based on the individual's personal and family history.
Comment:
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.
Comment:
The TP53 c.638G>A (p.Arg213Gln) variant has been reported in the published literature in individuals with late onset breast, ovarian, and choroid plexus carcinomas, as well as in affected individuals with Li-Fraumeni syndrome (PMIDs: 32019277 (2020), 31119730 (2020), 30720243 (2019), 26270727 (2015), 24728327 (2014), 23259501 (2012), 16736287 (2006)). It has also been observed as early onset in an affected individual with gray zone lymphoma (PMID: 30299350 (2019)). A yeast based functional study of this variant showed a lack of transcriptional activity (PMID: 1676287 (2006)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 213 of the TP53 protein (p.Arg213Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Li-Fraumeni syndrome (LFS) or LFS-associated malignancies (PMID: 16494995, 16736287, 17541742, 18208484, 19468865, 20522432, 23259501). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 135359). Invitae Evidence Modeling incorporating data from in vitro 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: 12826609, 16736287, 17606709, 21343334). For these reasons, this variant has been classified as Pathogenic.
Comment:
Criteria applied: PS3,PS4,PM5_STR,PM2_SUP
Comment:
This missense variant replaces arginine with glutamine at codon 213 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant results in the loss of DNA binding and transactivation activity of TP53 protein (PMID: 7885831, 10871862, 12826609, 16736287, 24384472). This variant has been reported in an individual affected with Li-Fraumeni syndrome (Color internal data) and in individuals meeting the Chompret criteria of Li-Fraumeni syndrome (PMID: 17541742, 23259501). In a large pedigree that meets the Birch criteria of Li-Fraumeni-like syndrome, this variant has been shown to segregate with late-onset breast cancer, ovarian cancer, colorectal cancer, renal cell cancer, melanoma, mesothelioma and lung cancer in 12 family members (PMID: 16736287). This variant has been observed in individuals not meeting Li-Fraumeni syndrome diagnostic criteria but affected with breast cancer (PMID: 17541742, 20522432, 31119730, 32019277; Color internal data) and sarcoma (PMID: 19468865). An analysis of the IARC TP53 germline variant dataset has shown this variant to exhibit reduced penetrance (PMID: 29076966). This variant has been identified in 1/251462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. This variant may display reduced penetrance relative to typical pathogenic TP53 variants. Medical management should be considered based on the individual's personal and family history.
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in adrenal cortex carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 30224644, 12826609). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 25743702, 17289876, 25490274, 11454518, 27165744, 24747642, 33534120).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 10871862). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24436047, 34166060, 24332040, 25768946, 26138366).
Comment:
The TP53 c.638G>A variant is predicted to result in the amino acid substitution p.Arg213Gln. This variant has been reported in individuals with Li-Fraumeni syndrome or related cancers (Ruijs et al. 2006. PubMed ID: 16736287; Table S1A, Monti et al. 2007. PubMed ID: 17606709; Arcand et al. 2008. PubMed ID: 17541742; Ruijs et al. 2010. PubMed ID: 20522432; Table S3, Sun et al. 2017. PubMed ID: 28724667; Table S3, Rana et al. 2019. PubMed ID: 31105275). Functional studies showed that this variant altered DNA-binding and transactivation activities (Table S1 and Table S3, Monti et al. 2011. PubMed ID: 21343334; Zhang et al. 2014. PubMed ID: 24384472; Zerdoumi et al. 2017. PubMed ID: 28369373). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and interpreted as pathogenic by most of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135359/). This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Detection of Germline Mutations in Breast Cancer Patients with Clinical Features of Hereditary Cancer Syndrome Using a Multi-Gene Panel Test. | Shin HC | Cancer research and treatment | 2020 | PMID: 32019277 |
| Prevalence and clinical impact of TP53 germline mutations in Chinese women with breast cancer. | Sheng S | International journal of cancer | 2020 | PMID: 31119730 |
| High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering. | Soussi T | Human mutation | 2019 | PMID: 30720243 |
| Gray Zone Lymphoma Arising in the Neck of a Teenager With a Germline Mutation in TP53. | Gatineau-Sailliant S | Journal of pediatric hematology/oncology | 2019 | PMID: 30299350 |
| The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
| Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
| A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
| The landscape of genomic alterations across childhood cancers. | Gröbner SN | Nature | 2018 | PMID: 29489754 |
| Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li-Fraumeni syndrome. | Amadou A | Current opinion in oncology | 2018 | PMID: 29076966 |
| Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history. | de Andrade KC | Human mutation | 2017 | PMID: 28861920 |
| Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage. | Zerdoumi Y | Human molecular genetics | 2017 | PMID: 28369373 |
| Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. | Döhner H | Blood | 2017 | PMID: 27895058 |
| The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. | Stengel A | Leukemia | 2017 | PMID: 27680515 |
| TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. | Welch JS | The New England journal of medicine | 2016 | PMID: 27959731 |
| TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. | Kadia TM | Cancer | 2016 | PMID: 27463065 |
| Genomic Classification and Prognosis in Acute Myeloid Leukemia. | Papaemmanuil E | The New England journal of medicine | 2016 | PMID: 27276561 |
| Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival. | Mullany LK | Neoplasia (New York, N.Y.) | 2015 | PMID: 26585234 |
| Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment. | Desmond A | JAMA oncology | 2015 | PMID: 26270727 |
| TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. | Hou HA | Blood cancer journal | 2015 | PMID: 26230955 |
| TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. | Ok CY | Journal of hematology & oncology | 2015 | PMID: 25952993 |
| Germline TP53 mutations is common in patients with two early-onset primary malignancies. | Chak BP | Clinical genetics | 2015 | PMID: 25293557 |
| Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
| The impact of R213 mutation on p53-mediated p21 activity. | Zhang Y | Biochimie | 2014 | PMID: 24384472 |
| Functional characterisation of p53 mutants identified in breast cancers with suboptimal responses to anthracyclines or mitomycin. | Berge EO | Biochimica et biophysica acta | 2013 | PMID: 23246812 |
| Number of rare germline CNVs and TP53 mutation types. | Silva AG | Orphanet journal of rare diseases | 2012 | PMID: 23259501 |
| A novel hierarchical prognostic model of AML solely based on molecular mutations. | Grossmann V | Blood | 2012 | PMID: 22915647 |
| TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. | Rücker FG | Blood | 2012 | PMID: 22186996 |
| Pleomorphic carcinoma of the lung arising in a patient with Li-Fraumeni syndrome: report of a case. | Kato T | Surgery today | 2011 | PMID: 21626334 |
| TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. | Jädersten M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21519010 |
| Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
| TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. | Ruijs MW | Journal of medical genetics | 2010 | PMID: 20522432 |
| Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
| TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset. | Pinto C | Familial cancer | 2009 | PMID: 19468865 |
| Choroid plexus carcinoma: a new case associated with a novel TP53 germ line mutation. | Becherini F | Neuropathology and applied neurobiology | 2008 | PMID: 18208484 |
| Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families. | Arcand SL | Breast cancer research and treatment | 2008 | PMID: 17541742 |
| Transcriptional functionality of germ line p53 mutants influences cancer phenotype. | Monti P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17606709 |
| The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. | Achatz MI | Cancer letters | 2007 | PMID: 16494995 |
| Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
| Late-onset common cancers in a kindred with an Arg213Gln TP53 germline mutation. | Ruijs MW | Familial cancer | 2006 | PMID: 16736287 |
| Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. | Kato S | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12826609 |
| A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. | Friedler A | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11782540 |
| Identification of a tumor-derived p53 mutant with novel transactivating selectivity. | Pan Y | Oncogene | 2000 | PMID: 10871862 |
| p53 binds single-stranded DNA ends through the C-terminal domain and internal DNA segments via the middle domain. | Bakalkin G | Nucleic acids research | 1995 | PMID: 7885831 |
| Clinical significance of p53 mutations in newly diagnosed Burkitt's lymphoma and acute lymphoblastic leukemia: a report of 48 cases. | Preudhomme C | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 1995 | PMID: 7707106 |
| Gain-of-function mutations of the p53 gene induce lymphohematopoietic metastatic potential and tissue invasiveness. | Hsiao M | The American journal of pathology | 1994 | PMID: 8080050 |
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Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Oncogenic
criteria provided, single submitter
|
Dec 29, 2025 | RCV006273527.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
Jan 15, 2024 | RCV006253810.1 | ||
|
Tier I (Strong)
- diagnostic
- supports diagnosis
(1)
|
May 19, 2025 | RCV006253811.1 |
Submissions - Somatic
|
Clinical impact
Help
The submitted somatic clinical impact for each SCV record. (Last evaluated) |
Review Status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (Jan 15, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Adrenal cortex carcinoma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007104732.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in adrenal cortex carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 30224644, 12826609). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 25743702, 17289876, 25490274, 11454518, 27165744, 24747642, 33534120). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Tier I (Strong)
- Diagnostic
-
supports diagnosis (May 19, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Embryonal rhabdomyosarcoma |
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
Accession: SCV007105605.1
First In ClinVar: Nov 22, 2025 Last updated: Nov 22, 2025 |
Comment:
show
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 10871862). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24436047, 34166060, 24332040, 25768946, 26138366). (less)
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
|
Oncogenicity
Help
The submitted oncogenicity classification for each SCV record. (Last evaluated) |
Review Status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Tumor type
Help
The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Help
This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Oncogenic
(Dec 29, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Neoplasm |
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV007129867.1
First In ClinVar: Jan 03, 2026 Last updated: Jan 03, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: somatic
Affected status: yes
|
|
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Comment:
The c.638G>A (p.Arg213Gln) variant in the TP53 gene has been reported in multiple families affected with Li-Fraumeni (LFS) or Li-Fraumeni-like (LFL) syndromes (PMID 16736287, 16494995, 19468865, 20522432) and is extremely rare in general population databases. Experimental studies have shown that this missense change affects TP53 protein function (PMID 8080050, 10871862, 17606709,17311302, 21343334). This variant is located within a mutational hotspot that encodes the DNA-binding domain of the p53 protein. Arg213 is a highly conserved residue and multiple lines of algorithms predict deleterious effect of the p.Arg213Gln change. Therefore, we classify this c.638G>A (p.Arg213Gln) variant as pathogenic.
Comment:
Variant summary: TP53 c.638G>A (p.Arg213Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four 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 251462 control chromosomes (gnomAD). c.638G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and associated cancers, and has been shown to segregate with disease within families (e.g. Ruijs_2006, Arcand_2008, Sheng_2020). These data indicate that the variant is very likely to be associated with disease. Experimental studies have shown that this missense change significantly affects the functional activity of the TP53 protein, diminishing its DNA-binding and transcriptional transactivation activities in yeast-based assays, and has been functionally classified as a partial deficiency (PD) or severe deficiency (SD) allele (PMID: 16736287, 21343334, 12826609, 17606709). Ten ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
c.638G>A, located in exon 6 of the TP53 gene, is predicted to result in the substitution of Arginine by Glutamine at codon 213, p.(Arg213Gln). This variant is found in 1/236928 alleles at a frequency of 0.0004% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C35; BayesDel: 0.5) (PP3). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609) and there is evidence of a dominant negative effect and loss of function according to Giacomelli 2018 (PMID: 30224644) (PS3). At least, this variant has been reported in 3 individuals affected with a TP53-related phenotype, which awards 2 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (internal data, PMID: 25293557, 16736287) (PS4_moderate). It has been reported in ClinVar (13x as pathogenic, 22x as likely pathogenic, 1x NA), LOVD (3x as pathogenic, 1x as NA) and CancerHotspots (25 somatic observations, PM1). Based on the currently available information, c.638G>A is classified as a likely pathogenic variant according to ClinGen-TP53 Guidelines version 1.4.
Comment:
The p.R213Q pathogenic mutation (also known as c.638G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 638. The arginine at codon 213 is replaced by glutamine, an amino acid with similar properties. In one study, p.R213Q was detected in a 3-month-old boy with choroid plexus carcinoma whose unaffected father was also found to carry the alteration (Becherini et al. Neuropathol. Appl. Neurobiol. 2008 Oct;34(5):564-8). Other studies have reported this alteration in individuals with clinical histories suspicious for Li-Fraumeni syndrome (LFS) (Achatz MI et al. Cancer Lett. 2007 Jan 8;245(1-2):96-102; Arcand SL et al. Breast Cancer Res Treat. 2008 Apr;108(3):399-408; Pinto C et al. Fam. Cancer. 2009 May;8(4):383-90; Ruijs MW et al. J. Med. Genet. 2010 Jun;47(6):421-8; Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). 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; Zerdoumi Y et al. Hum. Mol. Genet., 2017 07;26:2591-2602). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been detected in multiple families satisfying clinical diagnostic criteria for LFS to date (Ambry internal data). However, it has also been detected in individuals with atypical/mild LFS phenotypes, suggesting variable expressivity and penetrance (Ambry internal data). 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 available evidence, this alteration is classified as a pathogenic mutation.
Comment:
Published functional studies demonstrate a damaging effect: partial to non-functional transactivation activity, deficient in targeting the consensus binding sequencing of p53 in the regulatory region of the p21 gene, resulting in an inability to up-regulate cell cycle arrest and apoptosis (Pan 2000, Kato 2003, Monti 2011, Zhang 2014, Kotler 2018); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25268584, 16494995, 29979965, 28472496, 30224644, 28643165, 29058986, 25925845, 10871862, 14583457, 23259501, 16736287, 19468865, 8080050, 24728327, 1915267, 8492087, 21343334, 17606709, 24384472, 26270727, 26829319, 20522432, 28369373, 29076966, 18208484, 28861920, 29489754, 28724667, 30455982, 30675318, 30299350, 30720243, 30840781, 31119730, 30577483, 31481248, 31105275, 31447099, 33138793, 33818021, 17541742, 15510160)
Comment:
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.
Comment:
This missense variant replaces arginine with glutamine at codon 213 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of DNA binding and transactivation activity of TP53 protein (PMID: 7885831, 10871862, 12826609, 16736287, 24384472). This variant has been reported in an individual affected with Li-Fraumeni syndrome (Color internal data) and in individuals meeting the Chompret criteria of Li-Fraumeni syndrome (PMID: 17541742, 23259501). In a large pedigree that meets the Birch criteria of Li-Fraumeni-like syndrome, this variant has been shown to segregate with late-onset breast cancer, ovarian cancer, colorectal cancer, renal cell cancer, melanoma, mesothelioma and lung cancer in 12 family members (PMID: 16736287). This variant has been observed in individuals not meeting Li-Fraumeni syndrome diagnostic criteria but affected with breast cancer (PMID: 17541742, 20522432, 31119730, 32019277; Color internal data) and sarcoma (PMID: 19468865). An analysis of IARC's TP53 germline variant dataset has shown this variant to exhibit reduced penetrance (PMID: 29076966). This variant has been identified in 1/251462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. This variant may display reduced penetrance relative to typical pathogenic TP53 variants. Medical management should be considered based on the individual's personal and family history.
Comment:
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.
Comment:
The TP53 c.638G>A (p.Arg213Gln) variant has been reported in the published literature in individuals with late onset breast, ovarian, and choroid plexus carcinomas, as well as in affected individuals with Li-Fraumeni syndrome (PMIDs: 32019277 (2020), 31119730 (2020), 30720243 (2019), 26270727 (2015), 24728327 (2014), 23259501 (2012), 16736287 (2006)). It has also been observed as early onset in an affected individual with gray zone lymphoma (PMID: 30299350 (2019)). A yeast based functional study of this variant showed a lack of transcriptional activity (PMID: 1676287 (2006)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 213 of the TP53 protein (p.Arg213Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Li-Fraumeni syndrome (LFS) or LFS-associated malignancies (PMID: 16494995, 16736287, 17541742, 18208484, 19468865, 20522432, 23259501). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 135359). Invitae Evidence Modeling incorporating data from in vitro 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: 12826609, 16736287, 17606709, 21343334). For these reasons, this variant has been classified as Pathogenic.
Comment:
Criteria applied: PS3,PS4,PM5_STR,PM2_SUP
Comment:
This missense variant replaces arginine with glutamine at codon 213 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant results in the loss of DNA binding and transactivation activity of TP53 protein (PMID: 7885831, 10871862, 12826609, 16736287, 24384472). This variant has been reported in an individual affected with Li-Fraumeni syndrome (Color internal data) and in individuals meeting the Chompret criteria of Li-Fraumeni syndrome (PMID: 17541742, 23259501). In a large pedigree that meets the Birch criteria of Li-Fraumeni-like syndrome, this variant has been shown to segregate with late-onset breast cancer, ovarian cancer, colorectal cancer, renal cell cancer, melanoma, mesothelioma and lung cancer in 12 family members (PMID: 16736287). This variant has been observed in individuals not meeting Li-Fraumeni syndrome diagnostic criteria but affected with breast cancer (PMID: 17541742, 20522432, 31119730, 32019277; Color internal data) and sarcoma (PMID: 19468865). An analysis of the IARC TP53 germline variant dataset has shown this variant to exhibit reduced penetrance (PMID: 29076966). This variant has been identified in 1/251462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. This variant may display reduced penetrance relative to typical pathogenic TP53 variants. Medical management should be considered based on the individual's personal and family history.
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in adrenal cortex carcinoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMIDs: 30224644, 12826609). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 25743702, 17289876, 25490274, 11454518, 27165744, 24747642, 33534120).
Comment:
Variant has Tier I (strong) clinical significance as a diagnostic inclusion criterion in embryonal rhabdomyosarcoma, based on the following evidence: 1) Documented in one or more cancer databases (e.g., St. Jude Pecan, COSMIC, CIViC, OncoKB). 2) Appears in one or more well-established professional guidelines (e.g., World Health Organization [WHO]; National Comprehensive Cancer Network [NCCN]) as providing diagnostic, prognostic, or therapeutic information. 3) Information in the literature supports potential biologic effect of variant (PMID: 10871862). 4) Diagnostic for a specific tumor type/classification based on well-powered studies with expert-level consensus (Evidence Level B; PMIDs: 24436047, 34166060, 24332040, 25768946, 26138366).
Comment:
The TP53 c.638G>A variant is predicted to result in the amino acid substitution p.Arg213Gln. This variant has been reported in individuals with Li-Fraumeni syndrome or related cancers (Ruijs et al. 2006. PubMed ID: 16736287; Table S1A, Monti et al. 2007. PubMed ID: 17606709; Arcand et al. 2008. PubMed ID: 17541742; Ruijs et al. 2010. PubMed ID: 20522432; Table S3, Sun et al. 2017. PubMed ID: 28724667; Table S3, Rana et al. 2019. PubMed ID: 31105275). Functional studies showed that this variant altered DNA-binding and transactivation activities (Table S1 and Table S3, Monti et al. 2011. PubMed ID: 21343334; Zhang et al. 2014. PubMed ID: 24384472; Zerdoumi et al. 2017. PubMed ID: 28369373). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and interpreted as pathogenic by most of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135359/). This variant is interpreted as pathogenic.
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium. | Shern JF | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2021 | PMID: 34166060 |
| What Did We Learn from the Molecular Biology of Adrenal Cortical Neoplasia? From Histopathology to Translational Genomics. | Juhlin CC | Endocrine pathology | 2021 | PMID: 33534120 |
| Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
| Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
| Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage. | Zerdoumi Y | Human molecular genetics | 2017 | PMID: 28369373 |
| Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma. | Zheng S | Cancer cell | 2016 | PMID: 27165744 |
| Integrated genetic and epigenetic analysis defines novel molecular subgroups in rhabdomyosarcoma. | Seki M | Nature communications | 2015 | PMID: 26138366 |
| Clonality and evolutionary history of rhabdomyosarcoma. | Chen L | PLoS genetics | 2015 | PMID: 25768946 |
| Genomic landscape of paediatric adrenocortical tumours. | Pinto EM | Nature communications | 2015 | PMID: 25743702 |
| Whole-exome sequencing characterizes the landscape of somatic mutations and copy number alterations in adrenocortical carcinoma. | Juhlin CC | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 25490274 |
| Germline TP53 mutations is common in patients with two early-onset primary malignancies. | Chak BP | Clinical genetics | 2015 | PMID: 25293557 |
| Integrated genomic characterization of adrenocortical carcinoma. | Assié G | Nature genetics | 2014 | PMID: 24747642 |
| Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. | Shern JF | Cancer discovery | 2014 | PMID: 24436047 |
| Targeting oxidative stress in embryonal rhabdomyosarcoma. | Chen X | Cancer cell | 2013 | PMID: 24332040 |
| TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. | Ruijs MW | Journal of medical genetics | 2010 | PMID: 20522432 |
| TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset. | Pinto C | Familial cancer | 2009 | PMID: 19468865 |
| Choroid plexus carcinoma: a new case associated with a novel TP53 germ line mutation. | Becherini F | Neuropathology and applied neurobiology | 2008 | PMID: 18208484 |
| Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families. | Arcand SL | Breast cancer research and treatment | 2008 | PMID: 17541742 |
| Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity. | Libè R | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17289876 |
| The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. | Achatz MI | Cancer letters | 2007 | PMID: 16494995 |
| Late-onset common cancers in a kindred with an Arg213Gln TP53 germline mutation. | Ruijs MW | Familial cancer | 2006 | PMID: 16736287 |
| Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. | Kato S | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12826609 |
| Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. | Kato S | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12826609 |
| Molecular analysis of CDKN1C and TP53 in sporadic adrenal tumors. | Barzon L | European journal of endocrinology | 2001 | PMID: 11454518 |
| Identification of a tumor-derived p53 mutant with novel transactivating selectivity. | Pan Y | Oncogene | 2000 | PMID: 10871862 |
| Gain-of-function mutations of the p53 gene induce lymphohematopoietic metastatic potential and tissue invasiveness. | Hsiao M | The American journal of pathology | 1994 | PMID: 8080050 |
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Text-mined citations for rs587778720 ...
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Record last updated Jan 03, 2026
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