VCV000012364.68 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(52)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate oncogenicity classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Oncogenic

criteria provided, single submitter

Variant Details

Identifiers

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

Variation ID: 12364 Accession: VCV000012364.68

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7673776 (GRCh38) [ NCBI UCSC ] 17: 7577094 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 19, 2014	Jun 17, 2024	Feb 14, 2024
Somatic - Oncogenicity	Aug 11, 2024	Aug 11, 2024	Jul 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.844C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Arg282Trp	missense
NM_000546.5:c.[844C>T]
NM_001126112.3:c.844C>T	NP_001119584.1:p.Arg282Trp	missense
NM_001126113.3:c.844C>T	NP_001119585.1:p.Arg282Trp	missense
NM_001126114.3:c.844C>T	NP_001119586.1:p.Arg282Trp	missense
NM_001126115.2:c.448C>T	NP_001119587.1:p.Arg150Trp	missense
NM_001126116.2:c.448C>T	NP_001119588.1:p.Arg150Trp	missense
NM_001126117.2:c.448C>T	NP_001119589.1:p.Arg150Trp	missense
NM_001126118.2:c.727C>T	NP_001119590.1:p.Arg243Trp	missense
NM_001276695.3:c.727C>T	NP_001263624.1:p.Arg243Trp	missense
NM_001276696.3:c.727C>T	NP_001263625.1:p.Arg243Trp	missense
NM_001276697.3:c.367C>T	NP_001263626.1:p.Arg123Trp	missense
NM_001276698.3:c.367C>T	NP_001263627.1:p.Arg123Trp	missense
NM_001276699.3:c.367C>T	NP_001263628.1:p.Arg123Trp	missense
NM_001276760.3:c.727C>T	NP_001263689.1:p.Arg243Trp	missense
NM_001276761.3:c.727C>T	NP_001263690.1:p.Arg243Trp	missense
NC_000017.11:g.7673776G>A
NC_000017.10:g.7577094G>A
NG_017013.2:g.18775C>T
LRG_321:g.18775C>T
LRG_321t1:c.844C>T	LRG_321p1:p.Arg282Trp
	P04637:p.Arg282Trp

... more HGVS ... less HGVS

Protein change

R282W, R150W, R243W, R123W

Other names

Canonical SPDI

NC_000017.11:7673775:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Links

ClinGen: CA000454 UniProtKB: P04637#VAR_006016 OMIM: 191170.0018 dbSNP: rs28934574 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TP53		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3367	3466

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Li-fraumeni-like syndrome	Pathogenic (1)	no assertion criteria provided	Jan 1, 1995	RCV000013161.25
Li-Fraumeni syndrome 1	Pathogenic/Likely pathogenic (11)	criteria provided, multiple submitters, no conflicts	Jul 7, 2023	RCV000144670.19
Hereditary cancer-predisposing syndrome	Pathogenic/Likely pathogenic (7)	criteria provided, multiple submitters, no conflicts	Jun 18, 2022	RCV000210145.17
Squamous cell lung carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000423580.4
Neoplasm of the large intestine	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000430759.4
Hepatocellular carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000431084.7
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 21, 2021	RCV000236400.15
Carcinoma of esophagus	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000436175.4
Squamous cell carcinoma of the skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000424430.4
Pancreatic adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000434706.4
Non-Hodgkin lymphoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000417906.4
Malignant melanoma of skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000420798.4
Li-Fraumeni syndrome	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 18, 2024	RCV000148905.27
Glioblastoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000422920.4
Prostate adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000426680.4
Breast neoplasm	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000433225.4
Gastric adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000435581.4
Squamous cell carcinoma of the head and neck	Pathogenic (2)	criteria provided, single submitter	-	RCV000441472.5
Papillary renal cell carcinoma type 1	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000442231.4
Malignant neoplasm of body of uterus	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000444687.4
Ovarian serous cystadenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000425909.4
Transitional cell carcinoma of the bladder	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000432561.4
Ovarian neoplasm	Likely pathogenic (1)	no assertion criteria provided	Dec 1, 2018	RCV000785546.5
Lung adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000437607.4
Neoplasm of brain	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000444544.4
Colorectal cancer	Pathogenic (1)	criteria provided, single submitter	-	RCV001270278.4
Astrocytoma, anaplastic Pleomorphic xanthoastrocytoma	Pathogenic (1)	criteria provided, single submitter	Nov 4, 2016	RCV000722016.5
Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype	Likely pathogenic (1)	criteria provided, single submitter	Feb 12, 2019	RCV003315223.4
Adrenocortical carcinoma, hereditary	Pathogenic (1)	criteria provided, single submitter	Feb 14, 2024	RCV004566738.1
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Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Feb 04, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV000680092.1 First in ClinVar: Mar 23, 2018 Last updated: Mar 23, 2018	Number of individuals with the variant: 3 Sex: male
Pathogenic (Nov 04, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pleomorphic xanthoastrocytoma Astrocytoma, anaplastic Affected status: yes Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV000853189.1 First in ClinVar: Nov 25, 2018 Last updated: Nov 25, 2018	Comment: 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 … (more) 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. (less) Sex: male
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000407070.3 First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019	Publications: PubMed (8) PubMed: 26878390‚ 1565143‚ 21761402‚ 1565144‚ 19468865‚ 25619955‚ 8829627‚ 19012332 Comment: 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 … (more) 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. (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: case-control	Colorectal cancer Affected status: yes Allele origin: somatic	Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo Accession: SCV001450497.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Publications: PubMed (2) PubMed: 30816478‚ 32000721 Age: 60-69 years Sex: female Geographic origin: Sri Lanka
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: case-control	Squamous cell carcinoma of the head and neck Affected status: yes Allele origin: somatic	Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo Accession: SCV001450496.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Publications: PubMed (1) PubMed: 30816478 Age: 60-69 years Sex: female Geographic origin: Sri Lanka
Pathogenic (May 21, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000292698.11 First in ClinVar: Jul 24, 2016 Last updated: Apr 17, 2019	Comment: 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., … (more) 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) (less)
Likely pathogenic (Jun 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002582345.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Likely pathogenic (Jun 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002583007.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Pathogenic (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000839109.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Likely pathogenic (Feb 12, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype Affected status: yes Allele origin: germline	Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital Accession: SCV004012928.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023
Pathogenic (Jul 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: unknown	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV004015238.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: 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 … (more) 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. (less)
Pathogenic (Dec 18, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004241252.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Publications: PubMed (26) PubMed: 17606709‚ 21343334‚ 20407015‚ 11370630‚ 21059199‚ 1349175‚ 22672556‚ 1565144‚ 1565143‚ 21305319‚ 26230955‚ 21519010‚ 27463065‚ 25952993‚ 22186996‚ 27680515‚ 27959731‚ 16818505‚ 27895058‚ 30327374‚ 24857548‚ 11782540‚ 23246812‚ 22915647‚ 26585234‚ 27276561 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000691656.3 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (18) PubMed: 1565143‚ 8402598‚ 8425176‚ 11370630‚ 12826609‚ 15958617‚ 16206219‚ 19468865‚ 21305319‚ 21343334‚ 21761402‚ 22672556‚ 25584008‚ 25619955‚ 28975465‚ 29979965‚ 30224644‚ 30709381 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adrenocortical carcinoma, hereditary Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005054335.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Nov 20, 2015)	criteria provided, single submitter (Shirts et al. (Genet Med 2016)) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV000266136.1 First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016	Number of individuals with the variant: 1 Clinical Features: breast cancer (present) Age: 20-29 years
Pathogenic (Apr 18, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000785099.2 First in ClinVar: Jul 14, 2018 Last updated: Jul 14, 2018	Publications: PubMed (9) PubMed: 24573247‚ 21761402‚ 17606709‚ 26014290‚ 22672556‚ 21343334‚ 21305319‚ 21059199‚ 26911350
Likely pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000821787.2 First in ClinVar: Oct 10, 2018 Last updated: Mar 25, 2020	Comment: 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 … (more) 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). (less)
Pathogenic (Jan 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: maternal	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV002030224.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (Aug 08, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002069228.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: 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 … (more) 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). (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002073337.1 First in ClinVar: Feb 03, 2022 Last updated: Feb 03, 2022	Comment: 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 … (more) 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. (less) Clinical Features: Neoplasm (present) , Ovarian neoplasm (present) , Breast carcinoma (present)
Pathogenic (Oct 31, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002532713.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The TP53 c.844C>T (p.R282W) variant has been reported in heterozygosity in numerous individuals with Li-Fraumeni or Li-Fraumeni-like syndrome (PMID: 1565143, 21059199, 21305319, 22672556, 25186627, 28369373). … (more) The TP53 c.844C>T (p.R282W) variant has been reported in heterozygosity in numerous individuals with Li-Fraumeni or Li-Fraumeni-like syndrome (PMID: 1565143, 21059199, 21305319, 22672556, 25186627, 28369373). The variant is located in the DNA binding domain of the TP53 protein. In silico tools suggest the impact of the variant on protein function is deleterious. Functional studies have shown that this variant disrupts the protein function by affecting protein folding and transactivation (PMID: 32475984, 21343334, 29979965). The variant also effects expression of p53 targeted genes (PMID: 28369373). An evaluation of cases reported to affect amino acid R282 found that these patients are more likely to have early-onset cancers and bone cancers (PMID: 24573247). It was observed in 1/113728 chromosomes of the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 12364). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (10) PubMed: 1565143‚ 21059199‚ 21305319‚ 22672556‚ 25186627‚ 28369373‚ 32475984‚ 21343334‚ 29979965‚ 24573247
Pathogenic (Aug 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581144.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS3, PS4_MOD, PM5, PM2_SUP, PP3	Number of individuals with the variant: 1 Sex: female
Pathogenic (Nov 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: germline	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn Accession: SCV002757862.1 First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022
Pathogenic (Apr 12, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004017907.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Publications: PubMed (9) PubMed: 1565144‚ 8425176‚ 16206219‚ 22672556‚ 33407742‚ 29581140‚ 1631137‚ 17015838‚ 29979965 Comment: 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, … (more) 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]. (less)
Pathogenic (Jan 18, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000253852.13 First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024	Publications: PubMed (11) PubMed: 28492532‚ 1565143‚ 1565144‚ 11370630‚ 21305319‚ 21761402‚ 25584008‚ 12826609‚ 29979965‚ 30224644‚ 17606709 Comment: 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 … (more) 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. (less)
Pathogenic (Nov 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848861.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Arg282Trp variant in TP53 has been reported in at least 4 individuals with features of Li-Fraumeni syndrome (Wasseman 2015 PMID: 25584008, Wu 2011 PMID: … (more) The p.Arg282Trp variant in TP53 has been reported in at least 4 individuals with features of Li-Fraumeni syndrome (Wasseman 2015 PMID: 25584008, Wu 2011 PMID: 21305319, Melhem-Bertrandt 2012 PMID: 21761402,Toguchida 1992 PMID: 1565143) and in ClinVar (Variation ID 12364). It has also been identified in 1/68022 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg282Trp variant is located in the DNA binding domain of the TP53 protein and in vitro functional assays support impact on protein function with loss of transactivation capacity and dominant negative effect, affecting several p53 isoforms (IARC TP53 database, Monti 2011 PMID: 21343334, Zerdoumi 2017 PMID: 28472496, Kato 2003 PMID: 12826609). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP criteria applied: PM1, PP3, PS3, PS4, PM2_Supporting. (less)
Pathogenic (Jun 29, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000581079.6 First in ClinVar: Mar 20, 2016 Last updated: May 01, 2024	Publications: PubMed (11) PubMed: 12826609‚ 24573247‚ 26014290‚ 26878390‚ 26911350‚ 27077130‚ 28472496‚ 28975465‚ 29581140‚ 29979965‚ 30224644 Comment: 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 … (more) 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. (less)
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Pancreatic adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509575.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Squamous cell lung carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509574.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509576.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Glioblastoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509577.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Transitional cell carcinoma of the bladder (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509581.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Prostate adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509580.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Ovarian serous cystadenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509583.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant neoplasm of body of uterus (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509585.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of brain (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509582.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Breast neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509578.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Renal cell carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509579.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Carcinoma of esophagus (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509584.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Squamous cell carcinoma of the skin (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509586.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant melanoma of skin (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509591.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Gastric adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509587.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Lymphoma, non-Hodgkin, familial (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509588.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of the large intestine (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509589.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509590.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Hepatocellular carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000509592.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T
Pathogenic (Aug 26, 2022)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV002589036.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Pathogenic (Jul 24, 2014)	no assertion criteria provided Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000190002.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014	Publications: PubMed (7) PubMed: 17606709‚ 21305319‚ 21059199‚ 19468865‚ 21761402‚ 11370630‚ 23161690
Likely benign (Jun 01, 2014)	no assertion criteria provided Method: research	Li-Fraumeni syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190651.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Pathogenic (Jan 01, 1995)	no assertion criteria provided Method: literature only	LI-FRAUMENI-LIKE SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033408.4 First in ClinVar: Apr 04, 2013 Last updated: Sep 04, 2016	Publications: PubMed (5) PubMed: 1565143‚ 8718514‚ 1349175‚ 1565144‚ 8401536 Comment on evidence: Toguchida et al. (1992) identified a CGG-to-TGG change at codon 282 of the p53 gene, resulting in substitution of tryptophan for arginine (R282W). The proband … (more) Toguchida et al. (1992) identified a CGG-to-TGG change at codon 282 of the p53 gene, resulting in substitution of tryptophan for arginine (R282W). The proband had osteosarcoma at age 10 years and had an extensive family history of malignant tumors with an unusual prevalence of gastric cancer on the paternal side. The germline mutation in this family was demonstrated not only by the proband, but also by the affected father and by 2 apparently healthy sisters, aged 15 and 9 years at the time of the study. Eeles (1995) classified this family as having Li-Fraumeni-like syndrome (see 151623). Iavarone et al. (1992) identified the R282W mutation. in a patient with multifocal osteogenic sarcoma. Further rearrangement of the residual wildtype allele was detected in tumor tissue. The germline R282W mutation was identified by Malkin et al. (1992) in a proband who had liposarcoma diagnosed at the age of 7 years and osteosarcoma at the age of 12 years. The R282W mutation was identified in an osteosarcoma by Smith-Sorensen et al. (1993). (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000692065.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018
Likely pathogenic (Dec 01, 2018)	no assertion criteria provided Method: research	Ovarian neoplasm Affected status: yes Allele origin: somatic	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne Accession: SCV000924118.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019
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Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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).

Comment:

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).

Comment:

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.

Comment:

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].

Comment:

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.

Comment:

The p.Arg282Trp variant in TP53 has been reported in at least 4 individuals with features of Li-Fraumeni syndrome (Wasseman 2015 PMID: 25584008, Wu 2011 PMID: 21305319, Melhem-Bertrandt 2012 PMID: 21761402,Toguchida 1992 PMID: 1565143) and in ClinVar (Variation ID 12364). It has also been identified in 1/68022 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg282Trp variant is located in the DNA binding domain of the TP53 protein and in vitro functional assays support impact on protein function with loss of transactivation capacity and dominant negative effect, affecting several p53 isoforms (IARC TP53 database, Monti 2011 PMID: 21343334, Zerdoumi 2017 PMID: 28472496, Kato 2003 PMID: 12826609). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP criteria applied: PM1, PP3, PS3, PS4, PM2_Supporting.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

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).

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Synchronous choroid plexus papilloma and Wilms tumor in a girl, disclosing a Li-Fraumeni syndrome.	Cruz O	Hereditary cancer in clinical practice	2021	PMID: 33407742
A rapid solubility assay of protein domain misfolding for pathogenicity assessment of rare DNA sequence variants.	Anderson CL	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32475984
Pattern of nucleotide variants of TP53 and their correlation with the expression of p53 and its downstream proteins in a Sri Lankan cohort of breast and colorectal cancer patients.	Manoharan V	BMC cancer	2020	PMID: 32000721
Nucleotide variants and protein expression of TP53 in a Sri Lankan cohort of patients with head and neck cancer.	Manoharan V	Molecular medicine reports	2019	PMID: 30816478
Prevalence of germline mutations in the TP53 gene in patients with early-onset breast cancer in the Mexican population.	Gallardo-Alvarado LN	BMC cancer	2019	PMID: 30709381
The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes.	McNamara CJ	Blood advances	2018	PMID: 30327374
Mutational processes shape the landscape of TP53 mutations in human cancer.	Giacomelli AO	Nature genetics	2018	PMID: 30224644
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.	Kotler E	Molecular cell	2018	PMID: 29979965
Transmission of a TP53 germline mutation from unaffected male carrier associated with pediatric glioblastoma in his child and gestational choriocarcinoma in his female partner.	Cotter JA	Cold Spring Harbor molecular case studies	2018	PMID: 29581140
Expanding the spectrum of germline variants in cancer.	Siraj AK	Human genetics	2017	PMID: 28975465
Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage.	Zerdoumi Y	Human molecular genetics	2017	PMID: 28472496
Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage.	Zerdoumi Y	Human molecular genetics	2017	PMID: 28369373
Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.	Döhner H	Blood	2017	PMID: 27895058
The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases.	Stengel A	Leukemia	2017	PMID: 27680515
TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.	Welch JS	The New England journal of medicine	2016	PMID: 27959731
TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes.	Kadia TM	Cancer	2016	PMID: 27463065
Genomic Classification and Prognosis in Acute Myeloid Leukemia.	Papaemmanuil E	The New England journal of medicine	2016	PMID: 27276561
Incidentalome from Genomic Sequencing: A Barrier to Personalized Medicine?	Jamuar SS	EBioMedicine	2016	PMID: 27077130
Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India.	Mannan AU	Journal of human genetics	2016	PMID: 26911350
Gain of function of mutant p53: R282W on the peak?	Zhang Y	Oncogenesis	2016	PMID: 26878390
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.	Chang MT	Nature biotechnology	2016	PMID: 26619011
Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival.	Mullany LK	Neoplasia (New York, N.Y.)	2015	PMID: 26585234
TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution.	Hou HA	Blood cancer journal	2015	PMID: 26230955
Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers.	Bougeard G	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2015	PMID: 26014290
TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases.	Ok CY	Journal of hematology & oncology	2015	PMID: 25952993
Candidate gene analysis of BRCA1/2 mutation-negative high-risk Russian breast cancer patients.	Sokolenko AP	Cancer letters	2015	PMID: 25619955
Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study.	Wasserman JD	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2015	PMID: 25584008
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.	Tung N	Cancer	2015	PMID: 25186627
Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation.	Zhou G	Molecular cell	2014	PMID: 24857548
Heterogeneity of Li-Fraumeni syndrome links to unequal gain-of-function effects of p53 mutations.	Xu J	Scientific reports	2014	PMID: 24573247
Functional characterisation of p53 mutants identified in breast cancers with suboptimal responses to anthracyclines or mitomycin.	Berge EO	Biochimica et biophysica acta	2013	PMID: 23246812
The TP53 website: an integrative resource centre for the TP53 mutation database and TP53 mutant analysis.	Leroy B	Nucleic acids research	2013	PMID: 23161690
A novel hierarchical prognostic model of AML solely based on molecular mutations.	Grossmann V	Blood	2012	PMID: 22915647
Late onset Li-Fraumeni Syndrome with bilateral breast cancer and other malignancies: case report and review of the literature.	Kast K	BMC cancer	2012	PMID: 22672556
TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome.	Rücker FG	Blood	2012	PMID: 22186996
Early onset HER2-positive breast cancer is associated with germline TP53 mutations.	Melhem-Bertrandt A	Cancer	2012	PMID: 21761402
TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression.	Jädersten M	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2011	PMID: 21519010
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes.	Monti P	Molecular cancer research : MCR	2011	PMID: 21343334
Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome.	Wu CC	Human genetics	2011	PMID: 21305319
Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome.	Heymann S	Radiation oncology (London, England)	2010	PMID: 21059199
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.	Jordan JJ	Molecular cancer research : MCR	2010	PMID: 20407015
TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset.	Pinto C	Familial cancer	2009	PMID: 19468865
Somatic TP53 mutation mosaicism in a patient with Li-Fraumeni syndrome.	Prochazkova K	American journal of medical genetics. Part A	2009	PMID: 19012332
Transcriptional functionality of germ line p53 mutants influences cancer phenotype.	Monti P	Clinical cancer research : an official journal of the American Association for Cancer Research	2007	PMID: 17606709
Structural basis for understanding oncogenic p53 mutations and designing rescue drugs.	Joerger AC	Proceedings of the National Academy of Sciences of the United States of America	2006	PMID: 17015838
Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y).	Ferrone M	Molecular cancer therapeutics	2006	PMID: 16818505
CGH evaluation of two de novo synchronous tumors in a child with a germline p53 mutation.	Roque L	Pediatric blood & cancer	2006	PMID: 16206219
Evaluation of the combined effect of p53 codon 72 polymorphism and hotspot mutations in response to anticancer drugs.	Vikhanskaya F	Clinical cancer research : an official journal of the American Association for Cancer Research	2005	PMID: 15958617
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.	Kato S	Proceedings of the National Academy of Sciences of the United States of America	2003	PMID: 12826609
A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants.	Friedler A	Proceedings of the National Academy of Sciences of the United States of America	2002	PMID: 11782540
Detection of 11 germline inactivating TP53 mutations and absence of TP63 and HCHK2 mutations in 17 French families with Li-Fraumeni or Li-Fraumeni-like syndrome.	Bougeard G	Journal of medical genetics	2001	PMID: 11370630
Molecular analysis of the TP53 gene in Barrett's adenocarcinoma.	Audrézet MP	Human mutation	1996	PMID: 8829627
Germline mutations in the TP53 gene.	Eeles RA	Cancer surveys	1995	PMID: 8718514
Screening for germ line p53 mutations in children with malignant tumors and a family history of cancer.	Brugières L	Cancer research	1993	PMID: 8425176
Germ-line p53 mutation is uncommon in patients with triple primary cancers.	Shiseki M	Cancer letters	1993	PMID: 8402598
Screening for TP53 mutations in osteosarcomas using constant denaturant gel electrophoresis (CDGE).	Smith-Sørensen B	Human mutation	1993	PMID: 8401536
Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein.	Frebourg T	Proceedings of the National Academy of Sciences of the United States of America	1992	PMID: 1631137
Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms.	Malkin D	The New England journal of medicine	1992	PMID: 1565144
Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma.	Toguchida J	The New England journal of medicine	1992	PMID: 1565143
Germ-line and somatic p53 gene mutations in multifocal osteogenic sarcoma.	Iavarone A	Proceedings of the National Academy of Sciences of the United States of America	1992	PMID: 1349175
http://docm.genome.wustl.edu/variants/ENST00000455263:c.844C>T	-	-	-	-
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Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Oncogenic criteria provided, single submitter	Jul 31, 2024	RCV004668718.1

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity classification for each SCV record. (Last evaluated)	Review Status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Tumor type Help The tumor type for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Oncogenic

(Jul 31, 2024)

(ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022)

Method: clinical testing

Neoplasm

Affected status: unknown

Allele origin: somatic

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Accession: SCV005094389.1
First In ClinVar: Aug 11, 2024
Last updated: Aug 11, 2024

Comment:

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.

Comment:

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).

Comment:

Citations for somatic classification of this variant

There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs28934574 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs28934574 ...