ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.638G>A (p.Arg213Gln) (rs587778720)

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Total submissions: 36
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123099 SCV000166400 pathogenic Li-Fraumeni syndrome 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 213 of the TP53 protein (p.Arg213Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (ExAC <0.01%). This variant has been reported in individuals and families with Li-Fraumeni syndrome (LFS) or LFS-associated malignancies (PMID: 18208484, 20522432, 16494995, 19468865, 23259501), and was shown to segregate with disease in two families (PMID: 17541742, 16736287). ClinVar contains an entry for this variant (Variation ID: 135359). 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000130072 SCV000184899 pathogenic Hereditary cancer-predisposing syndrome 2018-10-30 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 alteration is located in the functionally critical DNA binding domain, and has been shown to be deficient in transcriptional activation and exhibit a dominant negative effect in functional assays in yeast and human cells (Monti P et al. Mol. Cancer Res. 2011 Mar; 9(3):271-9; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9; Zerdoumi Y et al. Hum. Mol. Genet., 2017 07;26:2591-2602). Other functional studies have shown that p.R213Q is deficient in growth suppression in human H1299 cells (Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8). 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). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Color Health, Inc RCV000130072 SCV000292157 pathogenic Hereditary cancer-predisposing syndrome 2020-10-30 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 2019-10-17 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 a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; 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, 17541742, 28861920, 29489754, 28724667, 30455982, 30675318, 30299350, 30720243, 30840781, 31119730, 30577483, 31481248, 31105275, 31447099, 33138793, 33818021)
Laboratory for Molecular Medicine, Partners HealthCare 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 Karolinska University Hospital,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
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 Adrenocortical 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 Adenocarcinoma of prostate 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 Neoplasms 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 Renal cell carcinoma, papillary, 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 Adenocarcinoma of stomach 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
Human Genetics - Radboudumc,Radboudumc RCV000420734 SCV001953963 pathogenic not provided no assertion criteria provided clinical testing

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