NM_000546.6:c.799C>T

Variant names:

• chr17-7673821-G-A
• rs55832599
• NM_000546.6:c.799C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):​c.799C>T​(p.Arg267Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R267Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 2.31

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a strand (size 10) in uniprot entity P53_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7673820-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-7673821-G-A is Pathogenic according to our data. Variant chr17-7673821-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 141764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7673821-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6	c.799C>T	p.Arg267Trp	missense_variant	Exon 8 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.799C>T	p.Arg267Trp	missense_variant	Exon 8 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461072 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726772

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:22

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:5

Jan 10, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria was used: PM2_SUP, PP3_MOD; PS4_MOD; PS3_SUP. Since the variant has been observed in a healthy homozygote carrier, the variant may have low or variable penetrance (PMID: 30588330). -

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling incorporating data from in vitro 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. -

Feb 28, 2020

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 19, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:4

Dec 09, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Located in the critical DNA binding domain (PMID: 15510160); 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, 36703617, 36113475, 36628428, 37306523, 37987115, 38355628, 15510160) -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TP53: PM2, PM5, PS4:Moderate, PS3:Supporting -

Oct 21, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Pathogenic:4

Feb 28, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 21, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PS4_Moderate, PM1, PM2_Supporting, PP3_Moderate MR (17/08/23): PS3 (4) + PS4_supp (1) + PM1 (2) + PM2_supp (1) + PP3_mod (2) -> PAT (10) based on TP53 ClinGenEP specifications_1.2+ICO guidelines and Garrett. c.799C>T, located in exon 8 of the TP53 gene, is predicted to result in the substitution of Arginine by Tryptophan at codon 267, p.(Arg267Trp). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. In-silico tools predict a pathogenic effect of the variant on protein function (aGVGD: C65; BayesDel: 0.54) (PP3_moderate). Transactivation assays show a non-functional allele according to Kato 2003 (PMID: 12826609). A second assay based on in vitro growth assays in H1299 human cells from Kotler 2018 shows loss of function (RFS=-0.64, PS3) (PMID: 29979965). This variant has been reported at least in 2 families/individuals affected with with a TP53-related phenotype, which awards 1.5 points to this variant as per ClinGen SVI Recommendation for LFS/Chompret Criterion (PMID: 30588330, 28573494) (PS4_supporting). It has been identified in the following databases, ClinVar** (3x as pathogenic, 10x as likely pathogenic), LOVD (2x as pathogenic, 1x as likely pathogenic, 1x as not provided), CancerHotspots (15 somatic observations, PM1), TP53 database. Based on currently available information, the variant c.799C>T should be considered a pathogenic variant. -

Li-Fraumeni syndrome 1 Pathogenic:2

Jun 18, 2022

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]. -

Adrenocortical carcinoma, hereditary Pathogenic:2

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Pathogenic:1

Nov 15, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0585442:Bone osteosarcoma;C0699790:Carcinoma of colon;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lip and oral cavity carcinoma Pathogenic:1

Apr 30, 2019

Institute of Medical Sciences, Banaras Hindu University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

TP53-related disorder Pathogenic:1

Oct 01, 2024

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.2	.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.4	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.98, 0.97, 1.0	.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.
Vest4		0.98
MutPred		0.91		Loss of disorder (P = 0.0012);.;.;.;.;.;.;.;Loss of disorder (P = 0.0012);.;Loss of disorder (P = 0.0012);Loss of disorder (P = 0.0012);Loss of disorder (P = 0.0012);.;.;Loss of disorder (P = 0.0012);.;.;.;
MVP		0.99
MPC		0.28
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55832599; hg19: chr17-7577139; COSMIC: COSV52678166; COSMIC: COSV52678166;