VCV000141764.44 - ClinVar

NM_000546.6(TP53):c.799C>T (p.Arg267Trp)

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.

(18)

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

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000546.6(TP53):c.799C>T (p.Arg267Trp)

Variation ID: 141764 Accession: VCV000141764.44

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7673821 (GRCh38) [ NCBI UCSC ] 17: 7577139 (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	Jan 9, 2017	Sep 29, 2024	May 7, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.799C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Arg267Trp	missense
NM_001126112.3:c.799C>T	NP_001119584.1:p.Arg267Trp	missense
NM_001126113.3:c.799C>T	NP_001119585.1:p.Arg267Trp	missense
NM_001126114.3:c.799C>T	NP_001119586.1:p.Arg267Trp	missense
NM_001126115.2:c.403C>T	NP_001119587.1:p.Arg135Trp	missense
NM_001126116.2:c.403C>T	NP_001119588.1:p.Arg135Trp	missense
NM_001126117.2:c.403C>T	NP_001119589.1:p.Arg135Trp	missense
NM_001126118.2:c.682C>T	NP_001119590.1:p.Arg228Trp	missense
NM_001276695.3:c.682C>T	NP_001263624.1:p.Arg228Trp	missense
NM_001276696.3:c.682C>T	NP_001263625.1:p.Arg228Trp	missense
NM_001276697.3:c.322C>T	NP_001263626.1:p.Arg108Trp	missense
NM_001276698.3:c.322C>T	NP_001263627.1:p.Arg108Trp	missense
NM_001276699.3:c.322C>T	NP_001263628.1:p.Arg108Trp	missense
NM_001276760.3:c.682C>T	NP_001263689.1:p.Arg228Trp	missense
NM_001276761.3:c.682C>T	NP_001263690.1:p.Arg228Trp	missense
NC_000017.11:g.7673821G>A
NC_000017.10:g.7577139G>A
NG_017013.2:g.18730C>T
LRG_321:g.18730C>T
LRG_321t1:c.799C>T	LRG_321p1:p.Arg267Trp
	P04637:p.Arg267Trp

... more HGVS ... less HGVS

Protein change

R135W, R228W, R267W, R108W

Other names

Canonical SPDI

NC_000017.11:7673820: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Links

ClinGen: CA000423 UniProtKB: P04637#VAR_036507 dbSNP: rs55832599 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.
Hereditary cancer-predisposing syndrome	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Feb 28, 2024	RCV000130398.20
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 7, 2024	RCV000413074.11
Li-Fraumeni syndrome	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 18, 2023	RCV000538977.18
Adrenocortical carcinoma, hereditary Basal cell carcinoma, susceptibility to, 7 Bone osteosarcoma Carcinoma of colon Carcinoma of pancreas Choroid plexus papilloma Familial cancer of breast Glioma susceptibility 1 Hepatocellular carcinoma Li-Fraumeni syndrome 1 Nasopharyngeal carcinoma	Likely pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000763416.4
Familial cancer of breast	Pathogenic (1)	criteria provided, single submitter	May 4, 2022	RCV002247507.3
Lip and oral cavity carcinoma	Pathogenic (1)	no assertion criteria provided	Apr 30, 2019	RCV001255676.3
Adrenocortical carcinoma, hereditary	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 4, 2024	RCV003460927.4
Li-Fraumeni syndrome 1	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 20, 2024	RCV002288637.3
Breast and/or ovarian cancer	Likely pathogenic (1)	criteria provided, single submitter	Nov 15, 2021	RCV003149899.3

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.
Likely pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Colorectal cancer Hepatocellular carcinoma Glioma susceptibility 1 Li-Fraumeni syndrome 1 Adrenocortical carcinoma, hereditary Bone osteosarcoma Familial pancreatic carcinoma Choroid plexus papilloma Nasopharyngeal carcinoma Basal cell carcinoma, susceptibility to, 7 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000894153.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Likely pathogenic (Feb 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni Syndrome Affected status: yes Allele origin: germline	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London Accession: SCV001429670.1 First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020	Comment: Data included in classification: UK family 1: Proband breast cancer at 42, mother breast cancer at 62 and melanoma, confirmed heterozygous for variant, maternal aunt … (more) Data included in classification: UK family 1: Proband breast cancer at 42, mother breast cancer at 62 and melanoma, confirmed heterozygous for variant, maternal aunt leukaemia 30s, another maternal aunt colorectal ca 66 and lung ca 77, maternal grandmother lung ca 74 and maternal grandfather brain tumour (meets Chompret criteria). Literature family 1: MDS at 52, breast fibroadenoma, melanoma in situ, sessile serrated adenoma, subependymoma (all in 50s) (Villani et al, 2017, PMID: 27501770). Literature family 2: proband breast cancer at 31 and soft tissue sarcoma at 43, relative with breast cancer at 34 (meets Chompret criteria) (Lovett et al, 2017, PMID:28573494). Literature family 3: proband breast cancer at 43, sibling with oligodendroglioma at 31yrs (Stoltz et al, 2018, PMID:29324801) Literature family 4: AlHarbi et al 2018 (PMID: 30588330) proband CPC at 2, sister CPC at 14 months, paternal aunt (heterozygous for variant) liver cancer at 49, paternal great uncle CRC at 55, paternal great aunt and great grandmother brain tumours (meets Chompret criteria) (PS4_mod). Absent from gnomAD (PM2_sup). Deleterious on SIFT, Polyphen, AlignGVGD, Bayesdel 0.542, Revel 0.917 (PP3_mod). Functional data: Non-functional on Kato et al, 2003(PMID: 12826609); impaired function on Fulci et al, 2002: PMID: 12019170), Wang et al, 2013 (PMID: 24076587), Perez et al, 2016 (PMID: 27022024) (PS3_strong). Additional data (not included in classification): 5 classifications of likely pathogenic on ClinVar. Unaffected 38 year old homozygote (AlHarbi et al, 2018, PMID: 30588330). Wang et al, 2013 (PMID:23484829): variant reported but no family information available. AlHarbi et al 2018 (Stoltz et al, 2018 (PMID: 29324801) variant segregates with multiple relatives with cancer diagnoses, but also with unaffected relatives. (less) Number of individuals with the variant: 1 Geographic origin: UK Testing laboratory: UK Molecular Diagnostic Labs
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002519887.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
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: SCV002582354.1 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: SCV002583015.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Likely pathogenic (Sep 19, 2022)	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: SCV002598661.1 First in ClinVar: Nov 05, 2022 Last updated: Nov 05, 2022	Publications: PubMed (26) PubMed: 17606709‚ 21343334‚ 20407015‚ 26230955‚ 21519010‚ 27463065‚ 25952993‚ 22186996‚ 27680515‚ 27959731‚ 16861262‚ 16818505‚ 27895058‚ 30327374‚ 11782540‚ 23246812‚ 22915647‚ 26585234‚ 24076587‚ 27276561‚ 31105275‚ 29324801‚ 30588330‚ 30840781‚ 28573494‚ 27501770 Comment: Variant summary: TP53 c.799C>T (p.Arg267Trp) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Five … (more) Variant summary: TP53 c.799C>T (p.Arg267Trp) results in a non-conservative amino acid change located in the p53, 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 was absent in 248996 control chromosomes (gnomAD). c.799C>T has been reported in the literature in individuals affected with Li-Fraumeni Syndrome and various types of cancer (examples: Villani_2016, llovet_2017, Stoltze_2018, AlHarbi_2018, Fortuno_2019, and Rana_2019). However, it has also been reported in unaffected individuals including one homozygote, reflecting possible lower penetrance of the variant (examples: AlHarbi_2018 and Stoltze_2018). Multiple publications have reported that this variant impairs the normal activity of the protein (examples: Wang_2014 and Dearth_2006). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3) and likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Likely pathogenic (Nov 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003838589.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868
Pathogenic (Oct 21, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004221374.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (20) PubMed: 29522266‚ 23484829‚ 30076369‚ 16861262‚ 21761402‚ 24076587‚ 27501770‚ 28573494‚ 29324801‚ 30588330‚ 31775759‚ 30287823‚ 33471991‚ 34240179‚ 30840781‚ 31567591‚ 32832836‚ 31105275‚ 29979965‚ 12826609 Comment: This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals that meet … (more) This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals that meet the criteria for Li-Fraumeni syndrome (LFS) (PMID: 30588330 (2018), 29324801 (2018), 28573494 (2017)). The variant is reported in individuals with breast cancer (PMID: 34240179 (2021), 33471991 (2021), 30287823 (2018), 29324801 (2018), 28573494 (2017), 21761402 (2012)), melanoma (31567591 (2020)), choroid plexus carcinoma (30588330 (2018)), liver cancer (30588330 (2018)), and myelodysplastic syndrome 27501770 (2016). Additionally, this variant is found in heterozygous and homozygous states in unaffected individuals with a family history of LFS (PMID: 30588330 (2018), 23484829 (2013)). Functional studies have found this variant impairs transcriptional activity, DNA binding, and apoptosis (PMID: 24076587 (2014), 16861262 (2007)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. (less)
Likely pathogenic (Dec 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020264.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Likely pathogenic (Oct 03, 2023)	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: SCV000686775.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (10) PubMed: 2932480‚ 9627118‚ 12019170‚ 12826609‚ 23484829‚ 24076587‚ 28573494‚ 29979965‚ 30588330‚ 34240179 Comment: This missense variant replaces arginine with tryptophan at codon 267 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant … (more) This missense variant replaces arginine with tryptophan at codon 267 in the DNA binding domain 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 the mutant protein to be defective in transactivation, apoptosis induction, and cell growth control activity (PMID: 9627118, 12019170, 12826609, 24076587, 29979965). This variant has been reported in individuals affected with early-onset breast cancer, glioma, and soft-tissue sarcoma, who meet the Chompret criteria for Li-Fraumeni syndrome (PMID: 28573494, 2932480, 34240179, Color internal data). This variant has also been reported in an unaffected individual with family history of Li-Fraumeni syndrome (PMID: 23484829). In one family meeting the Chompret criteria for Li-Fraumeni syndrome, this variant was observed in two heterozygous siblings affected with choroid plexus carcinomas and in their homozygous father who was healthy at age 39, indicating possibly low or variable penetrance of this variant (PMID: 30588330). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Pathogenic (Dec 08, 2023)	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: SCV000629873.10 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (11) PubMed: 28492532‚ 21761402‚ 27501770‚ 28573494‚ 29324801‚ 30588330‚ 12826609‚ 29979965‚ 30224644‚ 16861262‚ 24076587 Comment: This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 267 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 267 of the TP53 protein (p.Arg267Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 21761402, 27501770, 28573494, 29324801, 30588330). ClinVar contains an entry for this variant (Variation ID: 141764). 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, 16861262, 24076587). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Apr 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adrenocortical carcinoma, hereditary Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004809628.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Likely pathogenic (Feb 20, 2024)	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: SCV004931961.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 24076587‚ 27022024‚ 29979965‚ 28573494‚ 29324801 Comment: This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function … (more) This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 24076587, 27022024, 29979965]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28573494, 29324801]. (less)
Likely pathogenic (Feb 28, 2024)	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: SCV000185257.11 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 24076587‚ 27501770‚ 28573494‚ 29324801‚ 33471991‚ 35974385 Comment: The p.R267W variant (also known as c.799C>T) is located in coding exon 7 of the TP53 gene. This alteration results from a C to T … (more) The p.R267W variant (also known as c.799C>T) is located in coding exon 7 of the TP53 gene. This alteration results from a C to T substitution at nucleotide position 799. The arginine at codon 267 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in breast cancer patients (Melhem-Bertrandt A et al. Cancer 2012 Feb;118(4):908-13; Stoltze U et al. PLoS ONE, 2018 Jan;13:e0190050; Dorling et al. N Engl J Med. 2021 02;384:428-439) and in a female patient with myelodysplastic syndrome at age 52 (Villani A et al. Lancet Oncol., 2016 Sep;17:1295-305). It was also identified in two members of one family that met Li-Fraumeni syndrome (LFS) criteria (Llovet P et al. Fam. Cancer. 2017 Oct;16(4):567-575), in two siblings with choroid plexus carcinomas (AlHarbi M et al. NPJ Genom Med. 2018 Dec 19;3:35) and additional families with attenuated or classic LFS phenotypes (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and a moderate dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional functional assays conducted in human tumor cell lines demonstrated a lack of transactivation activity, deficient DNA binding, and an inability to suppress cell growth in response to DNA damaging agents (Wang B et al. Cell Death Differ. 2014 Apr; 21(4):521-32; Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8). To date, this alteration has not been detected in any cases of classic Li-Fraumeni syndrome (LFS) in our clinical cohort (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on current evidence, p.R267W is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS. Clinical correlation is advised. (less)
Pathogenic (Mar 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adrenocortical carcinoma, hereditary Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004206250.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (May 07, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000491277.5 First in ClinVar: Jan 09, 2017 Last updated: Sep 29, 2024	Comment: Observed in individuals with Li-Fraumeni-related and other cancers, but also present in unaffected individuals, with one unaffected homozygous adult reported (PMID: 21761402, 27501770, 28573494, 29085664, … (more) Observed in individuals with Li-Fraumeni-related and other cancers, but also present in unaffected individuals, with one unaffected homozygous adult reported (PMID: 21761402, 27501770, 28573494, 29085664, 30588330, 29324801, 35974385, 37377903); Published functional studies demonstrate a damaging effect: non-functional or decreased transactivation, and decreased or wildtype-like growth suppression activity (PMID: 9627118, 12826609, 16861262, 21232794, 25831048, 30224644, 29979965); Not observed at significant frequency in large population cohorts (gnomAD); 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: 27492616, 27022024, 21761402, 23484829, 15580553, 24868540, 26205736, 23536279, 22037554, 25171927, 26682952, 26342236, 26467027, 28445466, 28161563, 28915717, 29472312, 29515972, 16959974, 17311302, 12019170, 16941491, 19954513, 21060032, 24076587, 25831048, 18555592, 10557074, 12124823, 16322298, 27501770, 16861262, 9627118, 24164297, 21159888, 22205265, 25801821, 12934086, 9580667, 21232794, 12826609, 28446506, 28573494, 29085664, 17606709, 19367569, 21343334, 1562462, 30720243, 30840781, 31775759, 30588330, 29324801, 29805648, 31105275, 29979965, 31567591, 32817165, 32164171, 32832836, 30224644, 34240179, 35483880, 33153497, 37377903, 35974385, 37622400, 34273903, 33471991, 22915647, 27276561, 16818505, 11782540, 27959731, 23246812, 20407015, 22186996, 21519010, 26585234, 25952993, 27463065, 27680515, 30327374, 27895058, 37715966, 37327320, 15510160, 36703617, 36113475, 36628428, 37306523, 37987115, 38355628) (less)
Likely Pathogenic (Dec 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004823766.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (10) PubMed: 2932480‚ 9627118‚ 12019170‚ 12826609‚ 23484829‚ 24076587‚ 28573494‚ 29979965‚ 30588330‚ 34240179 Comment: This missense variant replaces arginine with tryptophan at codon 267 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant … (more) This missense variant replaces arginine with tryptophan at codon 267 in the DNA binding domain 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 the mutant protein to be defective in transactivation, apoptosis induction, and cell growth control activity (PMID: 9627118, 12019170, 12826609, 24076587, 29979965). This variant has been reported in individuals affected with early-onset breast cancer, glioma, and soft-tissue sarcoma, who meet the Chompret criteria for Li-Fraumeni syndrome (PMID: 28573494, 2932480, 34240179, Color internal data). This variant has also been reported in an unaffected individual with family history of Li-Fraumeni syndrome (PMID: 23484829). In one family meeting the Chompret criteria for Li-Fraumeni syndrome, this variant was observed in two heterozygous siblings affected with choroid plexus carcinomas and in their homozygous father who was healthy at age 39, indicating possibly low or variable penetrance of this variant (PMID: 30588330). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less) Number of individuals with the variant: 2
Pathogenic (Apr 30, 2019)	no assertion criteria provided Method: research	Lip and oral cavity carcinoma Affected status: yes Allele origin: somatic	Institute of Medical Sciences, Banaras Hindu University Accession: SCV001432241.1 First in ClinVar: Sep 18, 2020 Last updated: Sep 18, 2020	Publications: PubMed (1) PubMed: 31775759
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Comment:

Data included in classification: UK family 1: Proband breast cancer at 42, mother breast cancer at 62 and melanoma, confirmed heterozygous for variant, maternal aunt leukaemia 30s, another maternal aunt colorectal ca 66 and lung ca 77, maternal grandmother lung ca 74 and maternal grandfather brain tumour (meets Chompret criteria). Literature family 1: MDS at 52, breast fibroadenoma, melanoma in situ, sessile serrated adenoma, subependymoma (all in 50s) (Villani et al, 2017, PMID: 27501770). Literature family 2: proband breast cancer at 31 and soft tissue sarcoma at 43, relative with breast cancer at 34 (meets Chompret criteria) (Lovett et al, 2017, PMID:28573494). Literature family 3: proband breast cancer at 43, sibling with oligodendroglioma at 31yrs (Stoltz et al, 2018, PMID:29324801) Literature family 4: AlHarbi et al 2018 (PMID: 30588330) proband CPC at 2, sister CPC at 14 months, paternal aunt (heterozygous for variant) liver cancer at 49, paternal great uncle CRC at 55, paternal great aunt and great grandmother brain tumours (meets Chompret criteria) (PS4_mod). Absent from gnomAD (PM2_sup). Deleterious on SIFT, Polyphen, AlignGVGD, Bayesdel 0.542, Revel 0.917 (PP3_mod). Functional data: Non-functional on Kato et al, 2003(PMID: 12826609); impaired function on Fulci et al, 2002: PMID: 12019170), Wang et al, 2013 (PMID: 24076587), Perez et al, 2016 (PMID: 27022024) (PS3_strong). Additional data (not included in classification): 5 classifications of likely pathogenic on ClinVar. Unaffected 38 year old homozygote (AlHarbi et al, 2018, PMID: 30588330). Wang et al, 2013 (PMID:23484829): variant reported but no family information available. AlHarbi et al 2018 (Stoltz et al, 2018 (PMID: 29324801) variant segregates with multiple relatives with cancer diagnoses, but also with unaffected relatives.

Comment:

Variant summary: TP53 c.799C>T (p.Arg267Trp) results in a non-conservative amino acid change located in the p53, 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 was absent in 248996 control chromosomes (gnomAD). c.799C>T has been reported in the literature in individuals affected with Li-Fraumeni Syndrome and various types of cancer (examples: Villani_2016, llovet_2017, Stoltze_2018, AlHarbi_2018, Fortuno_2019, and Rana_2019). However, it has also been reported in unaffected individuals including one homozygote, reflecting possible lower penetrance of the variant (examples: AlHarbi_2018 and Stoltze_2018). Multiple publications have reported that this variant impairs the normal activity of the protein (examples: Wang_2014 and Dearth_2006). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3) and likely pathogenic (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals that meet the criteria for Li-Fraumeni syndrome (LFS) (PMID: 30588330 (2018), 29324801 (2018), 28573494 (2017)). The variant is reported in individuals with breast cancer (PMID: 34240179 (2021), 33471991 (2021), 30287823 (2018), 29324801 (2018), 28573494 (2017), 21761402 (2012)), melanoma (31567591 (2020)), choroid plexus carcinoma (30588330 (2018)), liver cancer (30588330 (2018)), and myelodysplastic syndrome 27501770 (2016). Additionally, this variant is found in heterozygous and homozygous states in unaffected individuals with a family history of LFS (PMID: 30588330 (2018), 23484829 (2013)). Functional studies have found this variant impairs transcriptional activity, DNA binding, and apoptosis (PMID: 24076587 (2014), 16861262 (2007)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

Comment:

This missense variant replaces arginine with tryptophan at codon 267 in the DNA binding domain 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 the mutant protein to be defective in transactivation, apoptosis induction, and cell growth control activity (PMID: 9627118, 12019170, 12826609, 24076587, 29979965). This variant has been reported in individuals affected with early-onset breast cancer, glioma, and soft-tissue sarcoma, who meet the Chompret criteria for Li-Fraumeni syndrome (PMID: 28573494, 2932480, 34240179, Color internal data). This variant has also been reported in an unaffected individual with family history of Li-Fraumeni syndrome (PMID: 23484829). In one family meeting the Chompret criteria for Li-Fraumeni syndrome, this variant was observed in two heterozygous siblings affected with choroid plexus carcinomas and in their homozygous father who was healthy at age 39, indicating possibly low or variable penetrance of this variant (PMID: 30588330). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 267 of the TP53 protein (p.Arg267Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 21761402, 27501770, 28573494, 29324801, 30588330). ClinVar contains an entry for this variant (Variation ID: 141764). 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, 16861262, 24076587). For these reasons, this variant has been classified as Pathogenic.

Comment:

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 24076587, 27022024, 29979965]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28573494, 29324801].

Comment:

The p.R267W variant (also known as c.799C>T) is located in coding exon 7 of the TP53 gene. This alteration results from a C to T substitution at nucleotide position 799. The arginine at codon 267 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in breast cancer patients (Melhem-Bertrandt A et al. Cancer 2012 Feb;118(4):908-13; Stoltze U et al. PLoS ONE, 2018 Jan;13:e0190050; Dorling et al. N Engl J Med. 2021 02;384:428-439) and in a female patient with myelodysplastic syndrome at age 52 (Villani A et al. Lancet Oncol., 2016 Sep;17:1295-305). It was also identified in two members of one family that met Li-Fraumeni syndrome (LFS) criteria (Llovet P et al. Fam. Cancer. 2017 Oct;16(4):567-575), in two siblings with choroid plexus carcinomas (AlHarbi M et al. NPJ Genom Med. 2018 Dec 19;3:35) and additional families with attenuated or classic LFS phenotypes (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and a moderate dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional functional assays conducted in human tumor cell lines demonstrated a lack of transactivation activity, deficient DNA binding, and an inability to suppress cell growth in response to DNA damaging agents (Wang B et al. Cell Death Differ. 2014 Apr; 21(4):521-32; Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8). To date, this alteration has not been detected in any cases of classic Li-Fraumeni syndrome (LFS) in our clinical cohort (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on current evidence, p.R267W is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS. Clinical correlation is advised.

Comment:

Observed in individuals with Li-Fraumeni-related and other cancers, but also present in unaffected individuals, with one unaffected homozygous adult reported (PMID: 21761402, 27501770, 28573494, 29085664, 30588330, 29324801, 35974385, 37377903); Published functional studies demonstrate a damaging effect: non-functional or decreased transactivation, and decreased or wildtype-like growth suppression activity (PMID: 9627118, 12826609, 16861262, 21232794, 25831048, 30224644, 29979965); Not observed at significant frequency in large population cohorts (gnomAD); 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: 27492616, 27022024, 21761402, 23484829, 15580553, 24868540, 26205736, 23536279, 22037554, 25171927, 26682952, 26342236, 26467027, 28445466, 28161563, 28915717, 29472312, 29515972, 16959974, 17311302, 12019170, 16941491, 19954513, 21060032, 24076587, 25831048, 18555592, 10557074, 12124823, 16322298, 27501770, 16861262, 9627118, 24164297, 21159888, 22205265, 25801821, 12934086, 9580667, 21232794, 12826609, 28446506, 28573494, 29085664, 17606709, 19367569, 21343334, 1562462, 30720243, 30840781, 31775759, 30588330, 29324801, 29805648, 31105275, 29979965, 31567591, 32817165, 32164171, 32832836, 30224644, 34240179, 35483880, 33153497, 37377903, 35974385, 37622400, 34273903, 33471991, 22915647, 27276561, 16818505, 11782540, 27959731, 23246812, 20407015, 22186996, 21519010, 26585234, 25952993, 27463065, 27680515, 30327374, 27895058, 37715966, 37327320, 15510160, 36703617, 36113475, 36628428, 37306523, 37987115, 38355628)

Comment:

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genotype-phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry.	Penkert J	Journal of hematology & oncology	2022	PMID: 35974385
Paired Tumor-Normal Sequencing Provides Insights Into the TP53-Related Cancer Spectrum in Patients With Li-Fraumeni Syndrome.	Ceyhan-Birsoy O	Journal of the National Cancer Institute	2021	PMID: 34240179
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.	Matejcic M	JCO precision oncology	2020	PMID: 32832836
Targeted germline sequencing of patients with three or more primary melanomas reveals high rate of pathogenic variants.	Li C	Melanoma research	2020	PMID: 31567591
Mutational spectrum of tobacco associated oral squamous carcinoma and its therapeutic significance.	Batta N	World journal of surgical oncology	2019	PMID: 31775759
Genotype-phenotype associations among panel-based TP53+ subjects.	Rana HQ	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 31105275
A quantitative model to predict pathogenicity of missense variants in the TP53 gene.	Fortuno C	Human mutation	2019	PMID: 30840781
Rare TP53 variant associated with Li-Fraumeni syndrome exhibits variable penetrance in a Saudi family.	AlHarbi M	NPJ genomic medicine	2018	PMID: 30588330
The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes.	McNamara CJ	Blood advances	2018	PMID: 30327374
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.	Momozawa Y	Nature communications	2018	PMID: 30287823
Mutational processes shape the landscape of TP53 mutations in human cancer.	Giacomelli AO	Nature genetics	2018	PMID: 30224644
Identification and characterization of TP53 gene Allele Dropout in Li-Fraumeni syndrome and Oral cancer cohorts.	Haque MM	Scientific reports	2018	PMID: 30076369
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.	Kotler E	Molecular cell	2018	PMID: 29979965
Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer.	Hauke J	Cancer medicine	2018	PMID: 29522266
Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark.	Stoltze U	PloS one	2018	PMID: 29324801
A novel TP53 germline inframe deletion identified in a Spanish series of Li-fraumeni syndrome suspected families.	Llovet P	Familial cancer	2017	PMID: 28573494
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
Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study.	Villani A	The Lancet. Oncology	2016	PMID: 27501770
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
Modeling the Etiology of p53-mutated Cancer Cells.	Perez RE	The Journal of biological chemistry	2016	PMID: 27022024
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
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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Mapping the p53 transcriptome universe using p53 natural polymorphs.	Wang B	Cell death and differentiation	2014	PMID: 24076587
Increased oxidative metabolism in the Li-Fraumeni syndrome.	Wang PY	The New England journal of medicine	2013	PMID: 23484829
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
A novel hierarchical prognostic model of AML solely based on molecular mutations.	Grossmann V	Blood	2012	PMID: 22915647
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
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.	Jordan JJ	Molecular cancer research : MCR	2010	PMID: 20407015
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
Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers.	Dearth LR	Carcinogenesis	2007	PMID: 16861262
Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y).	Ferrone M	Molecular cancer therapeutics	2006	PMID: 16818505
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
Initiation of human astrocytoma by clonal evolution of cells with progressive loss of p53 functions in a patient with a 283H TP53 germ-line mutation: evidence for a precursor lesion.	Fulci G	Cancer research	2002	PMID: 12019170
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
Human tumor-derived p53 proteins exhibit binding site selectivity and temperature sensitivity for transactivation in a yeast-based assay.	Di Como CJ	Oncogene	1998	PMID: 9627118
Cardiac gated MR imaging of cerebrospinal fluid flow.	Bergstrand G	Journal of computer assisted tomography	1985	PMID: 2932480
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Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000546.6(TP53):c.799C>T (p.Arg267Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs55832599 ...