17-7673821-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_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
NM_000546.6 missense
Scores
13
5
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TP53 | NM_000546.6 | c.799C>T | p.Arg267Trp | missense_variant | 8/11 | ENST00000269305.9 | NP_000537.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TP53 | ENST00000269305.9 | c.799C>T | p.Arg267Trp | missense_variant | 8/11 | 1 | NM_000546.6 | ENSP00000269305 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461072Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726772
GnomAD4 exome
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3
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1461072
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Cov.:
33
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1
AN XY:
726772
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GnomAD4 genome
GnomAD4 genome
Cov.:
31
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 08, 2023 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Cancer Variant Interpretation Group UK, Institute of Cancer Research, London | Feb 28, 2020 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 19, 2022 | 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:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 07, 2024 | 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) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 09, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 21, 2022 | 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:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 03, 2023 | 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2024 | 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. - |
Li-Fraumeni syndrome 1 Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 20, 2024 | 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
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 05, 2024 | - - |
Breast and/or ovarian cancer Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 15, 2021 | - - |
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
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Lip and oral cavity carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Institute of Medical Sciences, Banaras Hindu University | Apr 30, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G
Pathogenic
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
MutPred
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
MPC
0.28
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at