ClinVar Miner

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

dbSNP: rs587778720
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Total submissions: 44
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123099 SCV000166400 pathogenic Li-Fraumeni syndrome 2023-12-14 criteria provided, single submitter clinical testing 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). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16736287, 17606709, 21343334). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000130072 SCV000184899 pathogenic Hereditary cancer-predisposing syndrome 2021-11-12 criteria provided, single submitter clinical testing 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.
Color Diagnostics, LLC DBA Color Health RCV000130072 SCV000292157 pathogenic Hereditary cancer-predisposing syndrome 2023-04-18 criteria provided, single submitter clinical testing 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.
GeneDx RCV000420734 SCV000517027 pathogenic not provided 2021-11-16 criteria provided, single submitter clinical testing 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)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000123099 SCV000731632 pathogenic Li-Fraumeni syndrome 2020-01-10 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000123099 SCV001434920 pathogenic Li-Fraumeni syndrome 2019-02-21 criteria provided, single submitter clinical testing 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.
Clinical Genetics and Genomics, Karolinska University Hospital RCV000420734 SCV001449717 pathogenic not provided 2018-03-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000420734 SCV001469324 pathogenic not provided 2020-01-13 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Two other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Inconclusive segregation with disease
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798386 SCV002042828 pathogenic Breast and/or ovarian cancer 2019-08-09 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000130072 SCV002582482 pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000144664 SCV002583142 pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000123099 SCV003800820 pathogenic Li-Fraumeni syndrome 2023-01-30 criteria provided, single submitter clinical testing 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000144664 SCV003843119 pathogenic Li-Fraumeni syndrome 1 2022-10-17 criteria provided, single submitter clinical testing 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV000144664 SCV003925607 pathogenic Li-Fraumeni syndrome 1 2023-04-19 criteria provided, single submitter clinical testing _x000D_ Criteria applied: PS3, PS4, PM5_STR, PM2_SUP
Baylor Genetics RCV003460862 SCV004206242 pathogenic Adrenocortical carcinoma, hereditary 2023-08-22 criteria provided, single submitter clinical testing
ITMI RCV000122176 SCV000086391 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000144664 SCV000189995 pathogenic Li-Fraumeni syndrome 1 2014-07-24 no assertion criteria provided clinical testing
Database of Curated Mutations (DoCM) RCV000419636 SCV000509196 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430755 SCV000509197 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441015 SCV000509198 likely pathogenic Adrenal cortex carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424188 SCV000509199 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430946 SCV000509200 likely pathogenic Prostate adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438582 SCV000509201 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420908 SCV000509202 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432016 SCV000509203 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444077 SCV000509204 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422008 SCV000509205 likely pathogenic Uterine carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432438 SCV000509206 likely pathogenic Nasopharyngeal neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444201 SCV000509207 likely pathogenic Adenoid cystic carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425846 SCV000509208 likely pathogenic Papillary renal cell carcinoma type 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436981 SCV000509209 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443346 SCV000509210 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427005 SCV000509211 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437236 SCV000509212 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420459 SCV000509213 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430601 SCV000509214 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438230 SCV000509215 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420595 SCV000509216 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428223 SCV000509217 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Oxford Haemato-Oncology Service, Oxford University Hospitals NHS Foundation Trust RCV000626448 SCV000734838 drug response Poly (ADP-Ribose) polymerase inhibitor response 2017-11-27 no assertion criteria provided clinical testing
Institute of Medical Sciences, Banaras Hindu University RCV001255672 SCV001432237 pathogenic Lip and oral cavity carcinoma 2019-04-30 no assertion criteria provided research
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000420734 SCV001905965 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000420734 SCV001953963 pathogenic not provided no assertion criteria provided clinical testing
BRCAlab, Lund University RCV000130072 SCV002589031 pathogenic Hereditary cancer-predisposing syndrome 2022-08-26 no assertion criteria provided clinical testing

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