ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.638G>A (p.Arg213Gln) (rs587778720)

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Total submissions: 30
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130072 SCV000184899 pathogenic Hereditary cancer-predisposing syndrome 2017-08-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position
Color RCV000130072 SCV000292157 pathogenic Hereditary cancer-predisposing syndrome 2015-02-13 criteria provided, single submitter 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 Neoplasm of the breast 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
GeneDx RCV000420734 SCV000517027 pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing This pathogenic variant is denoted TP53 c.638G>A at the cDNA level, p.Arg213Gln (R213Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has been reported in two children, one with a choroid plexus carcinoma and the other with spitzoid melanoma (Becherini 2008, Lu 2015). TP53 Arg213Gln has also been observed in at least four families, two of which are reported as meeting Chrompet criteria (Ruijs 2006, Pinto 2009, Silva 2012, Arcand 2015). Both Ruijs et al. (2006) and Pinto et al. (2009) describe two separate families presenting with onset of malignancies later than what is observed in classic Li-Fraumeni kindreds. While Monti et al. (2011) reported TP53 Arg213Gln as having partial transactivation activity, assays completed by Kato et al. (2003) found this variant to have non-functional transactivation activity per the International Agency for Research on Cancer TP53 database. Importantly, TP53 Arg213Gln has been shown to be 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, Zhang 2014), and Olivier et al. (2003) described codon 213 as a mutational hot spot, with variants at this residue identified in 4.7% of individuals with germline TP53 variants. TP53 Arg213Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider TP53 Arg213Gln to be pathogenic; however based on published case reports, it may not result in classic Li-Fraumeni syndrome.
ITMI RCV000122176 SCV000086391 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000123099 SCV000166400 pathogenic Li-Fraumeni syndrome 2018-11-12 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000123099 SCV000731632 pathogenic Li-Fraumeni syndrome 2017-06-12 criteria provided, single submitter clinical testing The p.Arg213Gln variant in TP53 has been reported in 5 individuals with a variet y of TP53-associated cancers (Ruijs et al. 2006, Arcand et al. 2008, Becherini e t al. 2008, Desmond et al. 2015) and segregated with disease in 11 affected rela tives from 1 family with Li-Fraumeni syndrome (Ruijs et al. 2006). This variant has also been reported in ClinVar, as both a germline and somatic variant (Varia tion ID 135359). Additionally, it has been identified in 1/22298 of Finnish chro mosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org/; dbSNP rs587778720). In vitro functional studies provide some evidence tha t the p.Arg213Gln variant may impact protein function (Hsiao et al. 1994, Ruijs et al. 2006, Zhang et al. 2014). In summary, this variant meets criteria to be c lassified as pathogenic for Li Fraumeni syndrome in an autosomal dominant manner based upon segregation studies, absence from controls and functional evidence.
Oxford Haemato-Oncology Service,Oxford University Hospitals NHS Foundation Trust RCV000626448 SCV000734838 drug response PARP Inhibitor response 2017-11-27 no assertion criteria provided clinical testing
Pathway Genomics RCV000144664 SCV000189995 pathogenic Li-Fraumeni syndrome 1 2014-07-24 no assertion criteria provided clinical testing

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