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

gnomAD frequency: 0.00001  dbSNP: rs28934574

Total submissions: 50

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000148905	SCV000253852	pathogenic	Li-Fraumeni syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 282 of the TP53 protein (p.Arg282Trp). This variant is present in population databases (rs28934574, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (LFS) or Li-Fraumeni-like syndrome (PMID: 1565143, 1565144, 11370630, 21305319, 21761402, 25584008). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12364). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 29979965, 30224644). 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	2021-05-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato et al., 2003; Scian et al., 2004; Dearth et al., 2007; Monti et al., 2011; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32658383, 32475984, 31980526, 31105275, 32098966, 31537539, 31081129, 31159747, 30840781, 31016814, 30720243, 30709381, 28472496, 25186627, 28975465, 29555771, 29752822, 28861920, 29581140, 15280671, 29979965, 29315962, 29506128, 29300620, 29237527, 27882657, 28534505, 27683180, 28091804, 28369373, 27680515, 28387325, 28527674, 27077130, 28397142, 25925845, 8402598, 19468865, 18669439, 1349175, 8425176, 10864200, 21761402, 22672556, 27501770, 27714481, 27619989, 26911350, 25385265, 26878390, 26014290, 25619955, 15077194, 21343334, 21305319, 25637381, 24651015, 24573247, 14583457, 16206219, 1565144, 25584008, 19012332, 11370630, 21059199, 1565143, 12517413, 21445056, 12917626, 12826609, 16861262, 1631137, 17606709)
Illumina Laboratory Services, 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	2021-06-29	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). 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). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on the available evidence, this alteration is classified as a pathogenic mutation.
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 Diagnostics, LLC DBA Color Health	RCV000210145	SCV000691656	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 282 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 causes reduced transactivation activity, dominant negative effect, and loss of function in human cell proliferation and growth suppression assays (PMID: 12826609, 15958617, 21343334, 29979965, 30224644). This variant has been reported in many individuals affected with breast cancer, Li-Fraumeni syndrome, and Li-Fraumeni-like syndrome meeting Chompret criteria, including several de novo cases (PMID: 8402598, 8425176, 11370630, 1565143, 16206219, 19468865, 21305319, 21761402, 22672556, 25584008, 25619955, 28975465, 30709381). This variant has been identified in 1/251410 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
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 Molecular Pathology, 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
Baylor Genetics	RCV000144670	SCV002030224	pathogenic	Li-Fraumeni syndrome 1	2021-01-06	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory, University of Chicago	RCV000236400	SCV002069228	pathogenic	not provided	2018-08-08	criteria provided, single submitter	clinical testing	DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.844C>T, in exon 8 that results in an amino acid change, p.Arg282Trp. The p.Arg282Trp change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg282Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in the EXAC database with a low population frequency of 0.002% (dbSNP rs28934574). The p.Arg282Trp pathogenic sequence change has previously been described in multiple unrelated individuals with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome, and has been observed in the de novo state in at least two affected individuals (Malkin et al., 1992; Bougeard et al., 2001; Pinto et al., 2009; Wu et al., 2011; Kast et al., 2012; Melhem-Bertrandt et al., 2012; Wasserman et al., 2015). Functional studies have provided evidence that the p.Arg282Trp sequence change has a dominant negative effect and leads to significantly reduced TP53 transcriptional activity in response to DNA damage (Zerdoumi et al., 2017).
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000144670	SCV002073337	pathogenic	Li-Fraumeni syndrome 1		criteria provided, single submitter	clinical testing	The missense variant p.R282W in TP53 (NM_000546.6) has been reported in multiple affected patients (Mannan AU et al; Siraj AK et al). Functional studies suggest a damaging effect (Zerdoumi Y et al). The variant has been submitted to ClinVar as Pathogenic. The p.R282W variant is observed in 1/1,13,728 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R282W missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 282 of TP53 is conserved in all mammalian species. The nucleotide c.844 in TP53 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Sema4, Sema4	RCV000210145	SCV002532713	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-31	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000144670	SCV002581144	pathogenic	Li-Fraumeni syndrome 1	2022-08-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000210145	SCV002582345	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000144670	SCV002583007	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000144670	SCV002757862	pathogenic	Li-Fraumeni syndrome 1	2022-11-07	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003315223	SCV004012928	likely pathogenic	Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype	2019-02-12	criteria provided, single submitter	research
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000144670	SCV004015238	pathogenic	Li-Fraumeni syndrome 1	2023-07-07	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. 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. The mutation database ClinVar contains entries for this variant (Variation ID:12364). Therefore, this variant is considered as pathogenic.
Myriad Genetics, Inc.	RCV000144670	SCV004017907	pathogenic	Li-Fraumeni syndrome 1	2023-04-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 1565144, 8425176, 16206219, 22672556, 33407742, 29581140]. Functional studies indicate this variant impacts protein function [PMID: 1631137, 17015838, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000148905	SCV004241252	pathogenic	Li-Fraumeni syndrome	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.844C>T (p.Arg282Trp) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251810 control chromosomes. c.844C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome. Experimental studies have shown the variant to have a damaging effect on protein function. The following publications have been ascertained in the context of this evaluation (PMID: 23246812, 11370630, 27895058, 16818505, 11782540, 22915647, 21059199, 26230955, 1349175, 21519010, 20407015, 27463065, 22672556, 1565144, 30327374, 17606709, 21343334, 26585234, 25952993, 27276561, 22186996, 27680515, 1565143, 27959731, 21305319, 24857548). 21 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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	Papillary renal cell carcinoma type 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426680	SCV000509580	likely pathogenic	Prostate adenocarcinoma	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	Gastric adenocarcinoma	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, University Hospital Cologne	RCV000785546	SCV000924118	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research
BRCAlab, Lund University	RCV000210145	SCV002589036	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-26	no assertion criteria provided	clinical testing