ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.637C>T (p.Arg213Ter) (rs397516436)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115730 SCV000186844 pathogenic Hereditary cancer-predisposing syndrome 2017-10-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000213050 SCV000149639 pathogenic not provided 2018-11-27 criteria provided, single submitter clinical testing This variant is denoted TP53 c.637C>T at the cDNA level and p.Arg213Ter (R213X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in multiple families with Li-Fraumeni syndrome (Frebourg 1995, Vahteristo 2001, Kato 2011, Masciari 2011, Fostira 2015). Functional protein microarray revealed that TP53 Arg213Ter greatly decreased DNA binding to multiple responsive elements in comparison to wild-type p53 (Malcikova 2010). We consider this variant to be pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785330 SCV000923898 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America RCV000780783 SCV000918325 pathogenic not specified 2017-12-22 criteria provided, single submitter clinical testing Variant summary: The TP53 c.637C>T (p.Arg213X) variant results in a premature termination codon, predicted to cause a truncated or absent TP53 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 246252 control chromosomes, but has been reported in numerous patients with LFS with co-segregation evidence (Frebourg_1995, Trahair_2007, Masciari_2011). A section of a NSCLC with the variant was negative for TP53 staining, suggesting the transcript is a target for nonsense mediated decay (Hashimoto_1999). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000036532 SCV000166399 pathogenic Li-Fraumeni syndrome 2018-11-28 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg213*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in multiple individuals and families affected with Li-Fraumeni syndrome (PMID: 7887414, 11479205, 16401470, 16534790, 21552135, 21626334). ClinVar contains an entry for this variant (Variation ID: 43590). Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000036532 SCV000060187 pathogenic Li-Fraumeni syndrome 2013-08-20 criteria provided, single submitter clinical testing The Arg213X variant in TP53 has been previously reported in the literature in se veral individuals with features consistent with or a clinical diagnosis of LFS ( Horio 1994, Frebourg 1995, Varley 1999, Vahteristo 2001, Wong 2006, Trahair 2007 , Ferrarini 2011). Varley et al. (1999) also observed loss of heterozygosity for TP53 in an adrenocortical carcinoma tumor from an individual with the germline Arg213X variant. This variant has been well described as a somatic variant in mu ltiple tumor types, including those found as part of LFS (COSMIC). The Arg213X v ariant leads to a premature stop at codon 213. From this DNA sequencing test, we cannot determine the effect this nucleotide change will have on the protein pro duced, but it is predicted to lead to a truncated or absent protein. Therefore, this variant is highly likely to be pathogenic.
Pathway Genomics RCV000144672 SCV000190005 pathogenic Li-Fraumeni syndrome 1 2014-07-24 no assertion criteria provided clinical testing

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