ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.844C>T (p.Arg282Trp) (rs28934574)

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Total submissions: 37
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000148905 SCV000253852 pathogenic Li-Fraumeni syndrome 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 282 of the TP53 protein (p.Arg282Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with Li-Fraumeni syndrome (LFS) or Li-Fraumeni-like syndrome (PMID: 25584008, 21305319, 21761402, 1565143, 11370630, 1565144). This variant has also been reported to occur de novo in affected individuals (PMID: 22672556, 19468865). ClinVar contains an entry for this variant (Variation ID: 12364). Experimental studies have shown that this missense change results in the loss of transactivation activity and therefore has been classified as a severe deficiency allele (PMID: 17606709, 12826609). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000210145 SCV000266136 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000236400 SCV000292698 pathogenic not provided 2018-10-16 criteria provided, single submitter clinical testing This pathogenic variant is denoted TP53 c.844C>T at the cDNA level, p.Arg282Trp (R282W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been observed in Li-Fraumeni and Li-Fraumeni-like families and has been reported to occur de novo in at least two affected individuals (Iavarone 1992, Malkin 1992, Toguchida 1992, Shiseki 1993, Chompret 2000, Bougeard 2001, Plon 2008, Pinto 2009, Prochazkova 2009, Heymann 2010, Kast 2012, Melham-Bretrandt 2012, Arcand 2015, Bougeard 2015). Multiple functional studies have shown that TP53 Arg282Trp results in loss of transcriptional activation and growth suppression activities (Frebourg 1992, Lu 2003, Monti 2003, Scian 2004, Dearth 2007, Monti 2011, Xu 2011, Kotler 2018), and this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg282Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the current evidence, we consider this variant to be pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000144670 SCV000407070 pathogenic Li-Fraumeni syndrome 1 2017-04-27 criteria provided, single submitter clinical testing The TP53 c.844C>T (p.Arg282Trp) variant is listed as a common somatic and germline variant in the IARC TP53 variant database (Arcand et al. 2015; Wassermann et al. 2015). Across a selection of the available literature the TP53 c.844C>T (p.Arg282Trp) variant has been identified in at least nine individuals with different types of cancer, all in a heterozygous state (Toguchida et al. 1992; Malkin et al. 1992; Audrezet et al. 1996; Prochazkova et al. 2009; Pinto et al. 2009; Melhem-Bertrandt et al. 2012; Sokolenko et al. 2015). The p.Arg282Trp variant has also been found in a heterozygous state in at least two asymptomatic family members. The variant was absent from 200 control individuals and is reported at a frequency of 0.0002 in the European American population of the Exome Sequencing Project. This frequency is based on two alleles in a region of good coverage so the variant is presumed to be rare. Functional studies using the p.Arg282Trp variant protein document that the variant destabilizes the protein, increases aggregation and alters signalling to increase cellular invasion (Zhang et al. 2016). Based on the collective evidence, the p.Arg282Trp variant is classified as pathogenic for Li-Fraumeni syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Ambry Genetics RCV000210145 SCV000581079 pathogenic Hereditary cancer-predisposing syndrome 2018-05-31 criteria provided, single submitter clinical testing ​The p.R282W pathogenic mutation (also known as c.844C>T), located in coding exon 7 of the TP53 gene, results from a C to T substitution at nucleotide position 844. The arginine at codon 282 is replaced by tryptophan, an amino acid with dissimilar properties. This pathogenic mutation has been reported in multiple individuals or families with Li-Fraumeni Syndrome (LFS) or LFS-like syndrome (Toguchida J et al. N. Eng. J. Med. 1992 May;326(20):1301-8; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Kast K et al. BMC Cancer. 2012 Jun;12:217; Mannan AU et al. J. Hum. Genet. 2016 Jun;61:515-22; Siraj AK et al. Hum. Genet. 2017 11;136:1431-1444). The p.R282W mutation is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, dominant negative effect, and predicted to affect several p53 isoforms in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9; Zerdoumi Y et al. Hum. Mol. Genet. 2017 07;26:2812). In an analysis of data from the p53 germline mutation database, mutations at position R282 were shown to have an association with early onset bone cancers (Xu J et al. Sci. Rep. 2014;4:4223). Based on the available evidence, this alteration is classified as a pathogenic mutation.
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000144670 SCV000680092 pathogenic Li-Fraumeni syndrome 1 2018-02-04 criteria provided, single submitter clinical testing
Color Health, Inc RCV000210145 SCV000691656 pathogenic Hereditary cancer-predisposing syndrome 2015-12-14 criteria provided, single submitter clinical testing
Counsyl RCV000144670 SCV000785099 pathogenic Li-Fraumeni syndrome 1 2017-04-18 criteria provided, single submitter clinical testing
GeneKor MSA RCV000210145 SCV000821787 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This sequence change replaces Arginine with Tryptophan at codon 282 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein which interacts with multiple proteins. There is a large physiochemical difference between arginine and tryptophan (Grantham Score 101).This variant is present in population databases at a very low frequency ( rs28934574, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 25584008, 21305319, 21761402, 1565143). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. In addition, experimental studies have shown that this variant affects TP53 transactivation activity at variable levels. In summary, this is a rare sequence change that is expected to affect the TP53 protein and cause disease.The mutation database Clinvar contains entries for this variant (Variation ID:12364).
Mendelics RCV000148905 SCV000839109 pathogenic Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000722016 SCV000853189 pathogenic Astrocytoma, anaplastic; Pleomorphic xanthoastrocytoma 2016-11-04 criteria provided, single submitter clinical testing This is a missense alteration in which a C is replaced by a T at coding nucleotide 844 and is predicted to change an Arginine to a Tryptophan at amino acid codon 282. Classification criteria: PS3, PM1, PM2, PP3, PP5.
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo RCV000441472 SCV001450496 pathogenic Squamous cell carcinoma of the head and neck criteria provided, single submitter case-control
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo RCV001270278 SCV001450497 pathogenic Colorectal cancer criteria provided, single submitter case-control
OMIM RCV000013161 SCV000033408 pathogenic Li-Fraumeni-like syndrome 1995-01-01 no assertion criteria provided literature only
Pathway Genomics RCV000144670 SCV000190002 pathogenic Li-Fraumeni syndrome 1 2014-07-24 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148905 SCV000190651 likely benign Li-Fraumeni syndrome 2014-06-01 no assertion criteria provided research
Database of Curated Mutations (DoCM) RCV000423580 SCV000509574 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434706 SCV000509575 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441472 SCV000509576 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422920 SCV000509577 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433225 SCV000509578 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442231 SCV000509579 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426680 SCV000509580 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432561 SCV000509581 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444544 SCV000509582 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425909 SCV000509583 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436175 SCV000509584 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444687 SCV000509585 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424430 SCV000509586 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435581 SCV000509587 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417906 SCV000509588 likely pathogenic Non-Hodgkin lymphoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430759 SCV000509589 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437607 SCV000509590 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420798 SCV000509591 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431084 SCV000509592 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000236400 SCV000692065 pathogenic not provided no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785546 SCV000924118 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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