TP53 c.638G>A, p.Arg213Gln
NM_000546.5:c.638G>A
COSMIC ID: COSM131466
Pathogenic
Under TP53-specific VCEP guidelines and standard ACMG rules, only PM2 (Supporting) and PP5 (Supporting) are met. No strong or moderate pathogenic criteria are satisfied, resulting in classification as a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
PP5
Genetic Information
Gene & Transcript Details
Gene
TP53
Transcript
NM_000546.6
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.3 | Alternative | 11 exons | Reverse |
| NM_000546.4 | Alternative | 11 exons | Reverse |
| NM_000546.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000546.5:c.638G>A
Protein Change
R213Q
Location
Exon 6
(Exon 6 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 213 in gene TP53
Alternate Identifiers
COSM131466
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.638G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
European (Finnish)
0.00462%
Rare
Global: 0.000398%
European (Finnish): 0.00462%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251462Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251462 alleles, homozygotes = 0) and at a higher frequency in the European (Finnish) population (MAF= 0.00462%, 1/21646 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
9 publications
Likely Pathogenic
Based on 22 submitter reviews in ClinVar
Submitter Breakdown
21 Path
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (9)
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.
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.
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.
proposed classification - variant undergoing re-assessment, contact laboratory
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (21 clinical laboratories) and as drug response (1 clinical laboratories) and as pathogenic (1 clinical laboratories) and as Likely pathogenic (1 clinical laboratories).
COSMIC ID
COSM131466
Recurrence
93 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
1280
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (1280 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 213 in gene TP53
Functional Summary
The TP53 R213Q variant has been functionally characterized and shown to be damaging. In vitro studies indicate that this mutation is inactivating, as it reduces the protein's ability to induce cell cycle arrest and apoptosis, and increases MDM2 expression. Additionally, it results in a mild increase in cell proliferation in culture and fails to inhibit tumor growth in animal models, suggesting a loss of TP53 protein function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.92
0.92
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 5.52primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: "PVS1 applies to null variants predicted to undergo nonsense-mediated decay (nonsense or frameshift variants upstream of p.Lys351)". The evidence for this variant shows it is a missense change (R213Q). Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: "PS1 Strong: Same amino acid change as a known pathogenic variant." There is no identical amino acid change at codon 213 previously classified as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines: "PS2 Very Strong: ≥8 points for confirmed de novo occurrence." There are no data on de novo status for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines: "PS3 Strong: Non-functional on Kato et al. data AND loss of function on another assay." The available functional evidence does not reference Kato, Giacomelli, Kotler or Kawaguchi assays as required by TP53-specific PS3. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: "PS4 Very Strong: ≥8 points from proband data." No proband or case–control data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: "PM1 Moderate: Missense variants within codons 175, 245, 248, 249, 273, 282." The variant affects codon 213, which is not listed as a TP53 hotspot codon. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: "PM2 Supporting: allele frequency <0.00003 in gnomAD." The variant has MAF = 0.00000398 (<0.00003). Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: "PM3 applies to recessive disorders for variants observed in trans." TP53 is associated with an autosomal dominant mechanism. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PM4 applies to protein length changes (in‐frame indels or stop‐loss variants)." This is a missense variant with no change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: "PM5 Moderate: Missense variant at an amino acid residue where one other pathogenic missense variant has been seen." There are no other TP53 pathogenic missense variants reported at codon 213 under VCEP specifications. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines: "PM6 applies to assumed de novo occurrence without confirmation." No data on de novo status are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: "PP1 Supporting: segregation in 3–4 meioses." No family segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "PP2 applies to missense variants in genes with low rate of benign variation where missense is a common mechanism." TP53 has numerous benign and pathogenic missense variants. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: "PP3 Supporting: BayesDel score ≥0.16 or aGVGD C25-C55." In silico evidence provided is REVEL (0.92) but no BayesDel or aGVGD data are available as required by TP53 VCEP. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines: "PP4 Supporting: phenotype specificity observed (VAF 5–35%)." No clinical phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines: "PP5: Reputable source reports the variant as pathogenic without available evidence." ClinVar reports this variant as Pathogenic by 21 laboratories and Likely Pathogenic by additional submitters. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: "BA1 Stand‐Alone: Filtering allele frequency ≥0.001 in gnomAD." The variant MAF = 0.00000398 is < 0.001. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "BS1 Strong: Filtering allele frequency ≥0.0003 but <0.001 in a continental subpopulation." The variant MAF = 0.00000398 is < 0.0003. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: "BS2 Strong: ≥8 unrelated healthy elderly females without cancer." No such data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: "BS3 Strong: Functional assays show normal function on Kato et al. data AND no LOF on other assays." There is no evidence of normal function in the required assays. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: "BS4 Strong: Lack of segregation in affected family members." No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP1 applies to missense variants in a gene where only truncating variants are pathogenic." TP53 has many pathogenic missense variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP2 applies when the variant is in trans with a pathogenic variant in a dominant gene." No such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP3 applies to in‐frame indels in repetitive regions." This is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: "BP4 Supporting: BayesDel < 0.16 and no splicing impact." No BayesDel or splicing data are available. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP5 applies when an alternate genetic cause is present." No alternate cause data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: "BP6 applies when a reputable source reports the variant as benign." No such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines: "BP7 Supporting: synonymous or intronic variants with no splicing impact." This is a missense variant. Therefore, this criterion is not applied.