ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.844C>T (p.Arg282Trp) (rs28934574)

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Total submissions: 35
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210145 SCV000581079 pathogenic Hereditary cancer-predisposing syndrome 2017-04-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses),Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position,Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family
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
CSER_CC_NCGL; University of Washington Medical Center RCV000148905 SCV000190651 likely benign Li-Fraumeni syndrome 2014-06-01 no assertion criteria provided research
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.
Color 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
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 Neoplasm of the breast 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
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.
GeneKor MSA RCV000210145 SCV000821787 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785546 SCV000924118 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
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.
Invitae RCV000148905 SCV000253852 pathogenic Li-Fraumeni syndrome 2018-12-03 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 reported 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 the 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000236400 SCV000692065 pathogenic not provided no assertion criteria provided clinical testing
Mendelics RCV000148905 SCV000839109 pathogenic Li-Fraumeni syndrome 2018-07-02 criteria provided, single submitter clinical testing
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
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

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