17-7674893-C-T
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_000546.6(TP53):c.638G>A(p.Arg213Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
Publications
- breast cancerInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
- Li-Fraumeni syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
- Li-Fraumeni syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
- adrenocortical carcinoma, hereditaryInheritance: AD Classification: STRONG Submitted by: Ambry Genetics
- sarcomaInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- bone marrow failure syndrome 5Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- colorectal cancerInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- choroid plexus carcinomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TP53 | NM_000546.6 | MANE Select | c.638G>A | p.Arg213Gln | missense | Exon 6 of 11 | NP_000537.3 | ||
| TP53 | NM_001126112.3 | c.638G>A | p.Arg213Gln | missense | Exon 6 of 11 | NP_001119584.1 | |||
| TP53 | NM_001407262.1 | c.638G>A | p.Arg213Gln | missense | Exon 7 of 12 | NP_001394191.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TP53 | ENST00000269305.9 | TSL:1 MANE Select | c.638G>A | p.Arg213Gln | missense | Exon 6 of 11 | ENSP00000269305.4 | ||
| TP53 | ENST00000445888.6 | TSL:1 | c.638G>A | p.Arg213Gln | missense | Exon 6 of 11 | ENSP00000391478.2 | ||
| TP53 | ENST00000610292.4 | TSL:1 | c.521G>A | p.Arg174Gln | missense | Exon 5 of 10 | ENSP00000478219.1 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251462 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461878Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4AN XY: 727242 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome Pathogenic:5
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.
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.
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.
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.
proposed classification - variant undergoing re-assessment, contact laboratory
Li-Fraumeni syndrome 1 Pathogenic:5
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.
Criteria applied: PS3,PS4,PM5_STR,PM2_SUP
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.
not provided Pathogenic:5
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)
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.
Hereditary cancer-predisposing syndrome Pathogenic:5
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.
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.
Adrenocortical carcinoma, hereditary Pathogenic:1
Breast and/or ovarian cancer Pathogenic:1
TP53-related disorder Pathogenic:1
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.
Lip and oral cavity carcinoma Pathogenic:1
not specified Other:1
Poly (ADP-Ribose) polymerase inhibitor response Other:1
Possible response to PARP inhibitors.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at