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rs121913343

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000546.6(TP53):c.817C>T(p.Arg273Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,760 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. R273H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TP53
NM_000546.6 missense

Scores

11
6
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20U:1O:1

Conservation

PhyloP100: 5.73
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000546.6
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-7673802-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12366.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 17-7673803-G-A is Pathogenic according to our data. Variant chr17-7673803-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43594.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7673803-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TP53NM_000546.6 linkuse as main transcriptc.817C>T p.Arg273Cys missense_variant 8/11 ENST00000269305.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TP53ENST00000269305.9 linkuse as main transcriptc.817C>T p.Arg273Cys missense_variant 8/111 NM_000546.6 P1P04637-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152044
Hom.:
0
Cov.:
31
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250850
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135626
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000463
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461760
Hom.:
0
Cov.:
33
AF XY:
0.00000688
AC XY:
5
AN XY:
727184
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152044
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74256
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:20Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:5
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJun 18, 2022- -
Pathogenic, no assertion criteria providedclinical testingPathway GenomicsJul 24, 2014- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The missense variant p.R273C in TP53 (NM_000546.6) has previously been detected in multiple patients with Li-Fraumeni syndrome or Li-Fraumeni related cancers (Eeles et al, 1993). This missense variant causes the same amino acid change as a previously established pathogenic variant. Functional studies reveal that this variant leads to a severe deficiency of TP53 activity (Monti et al, 2011). Experimental studies have shown that this missense change disrupts the DNA-binding, transcriptional transactivation, and tumor suppressor activities of the TP53 protein (Malcikova et al, 2010). The p.R273C variant is observed in 1/18,372 (0.0054%) alleles from individuals of East Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.R273C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 273 of TP53 is conserved in all mammalian species. The nucleotide c.817 in TP53 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingHuman Genome Sequencing Center Clinical Lab, Baylor College of MedicineJul 06, 2017This c.817C>T (p.Arg273Cys) variant has previously been detected in multiple patients with Li-Fraumeni syndrome or Li-Fraumeni related cancers [PMID 8479749, 21535297, 21552135]. Functional data showed that this variant leads to a severe deficiency of TP53 activity [PMID 21343334, 24677579, 17606709]. The amino acid position 273 of the TP53 protein is a hot spot for pathogenic variants causing Li-Fraumeni syndrome: additional variants affecting the same amino acid at position 273 have been reported (p.Arg273Gly and p.Arg273His). This variant was observed in three heterozygous individuals in the gnomAD database (http://gnomad.broadinstitute.org/variant/17-7577121-G-A). This variant is highly conserved in mammals and computer-based algorithms predict this p.Arg273Cys change to be deleterious. It is thus classified as pathogenic. The next generation sequencing (NGS) reads indicated a skewed mutant to reference allele ratio (about 25% mutant), which was confirmed by Sanger sequencing, indicating mosaicism in this sample. Mosaic somatic pathogenic variants in cancer related genes, including TP53, have been reported in DNA extracted from blood samples in aging populations [PMID 25426837, 25426838, 25326804]. While an increase risk for hematologic cancer was reported in these studies, the clinical significance of these somatic variants in blood is currently unclear. While this variant is a known disease-causing variant observed in patients with Li-Fraumeni syndrome, considering the age of this individual, this finding may result from a somatic event observed in aging process. Studies in another tissue sample such as a skin biopsy is thus suggested to help clarify the clinical significance of this change. -
Pathogenic, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalFeb 03, 2022- -
not provided Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenSep 01, 2022TP53: PS3, PM1, PM2, PP4, PS4:Supporting -
Pathogenic, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo Clinic-- -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJul 27, 2021- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 22, 2023Published functional studies demonstrate a damaging effect: loss of growth suppression and apoptotic activities and non-functional transactivation (Kato et al., 2003; Dearth et al., 2007; Malcikova et al., 2010; Monti et al., 2011; Li et al., 2014; Giacomelli et al., 2018; Kotler et al., 2018); 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); This variant is associated with the following publications: (PMID: 11370630, 11315715, 7732013, 28915719, 28527674, 29958926, 27374712, 29489754, 20128691, 16861262, 17606709, 21343334, 21535297, 8479749, 21552135, 24677579, 7887414, 10864200, 11494139, 12695689, 19556618, 20443677, 26681312, 28387325, 28840050, 28717136, 28975465, 30720243, 30092803, 30796655, 30093976, 30840781, 31278746, 31559875, 15510160, 12826609, 35273153, 31105275, 31447099, 29922827, 34906214, 30224644, 29979965, 33245408, 32817165) -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 14, 2017- -
Li-Fraumeni syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 05, 2010The Arg273Cys variant has been reported in the literature in one individual with clinical features consistent with Li-Fraumeni Syndrome (LFS, Gonzales 2009). Th is individual had cancer as a teenager followed by two additional cancers in the ir twenties. Two other variants at the same amino acid position (Arg273His and A rg273Leu) have also been identified in individuals with features of LFS, and one of these variants was shown to have occurred de novo in a proband (Gonzalez 200 9). The Arg273Cys variant is the most common somatic mutation listed in the Cata logue of Somatic Mutations in Cancer (www.sanger.ac.uk/cosmic/) and this change is found in tumors throughout the body, including the central nervous system (10 tumors), haematopoietic and lymphoid tissue (5), bone (3), large intestine (2), and ovaries (1). Arg273 is highly conserved across divergent species and three bioinformatic algorithms predict this variant to affect protein function. Theref ore, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 08, 2023Variant summary: TP53 c.817C>T (p.Arg273Cys) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250850 control chromosomes. c.817C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (Masciari_2011, Khincha_2019, Rana_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function shows a severe decrease in promoter binding and transactivation capability ( Monti_2011, Malcikova_2010). The following publications have been ascertained in the context of this evaluation (PMID: 23612969, 21343334, 31212162, 31105275, 21552135, 20128691). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 13, 2024This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 273 of the TP53 protein (p.Arg273Cys). This variant is present in population databases (rs121913343, gnomAD 0.005%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 8479749, 17606709, 21535297, 21552135). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 43594). 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, 20128691, 24677579, 29979965, 30224644). This variant disrupts the p.Arg273 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565144, 8164043, 8479749, 17606709, 18685109, 20693561, 21535297, 21552135, 25584008; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJun 18, 2022- -
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 17, 2021The p.R273C pathogenic mutation (also known as c.817C>T), located in coding exon 7 of the TP53 gene, results from a C to T substitution at nucleotide position 817. The arginine at codon 273 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple families that met classic LFS or Chompret criteria (Janaviius R et al. Breast J. 2011;17(4):409-415; Masciari S et al. Genet. Med. 2011 Jul;13(7):651-7). This alteration is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and a dominant negative phenotype (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This position is characterized as a mutation hotspot and has been shown to be involved in DNA contact and binding (Martin AC et al. Hum. Mutat. 2002 Feb;19(2):149-64). Based on the available evidence, this alteration is classified as a pathogenic mutation. -
Adrenocortical carcinoma, hereditary Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsSep 05, 2023- -
Neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Jul 14, 2015- -
Neoplasm of ovary Pathogenic:1
Likely pathogenic, no assertion criteria providedresearchGerman Consortium for Hereditary Breast and Ovarian Cancer, University Hospital CologneDec 01, 2018- -
Acute myeloid leukemia Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Oct 02, 2014- -
Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Jul 14, 2015- -
Malignant tumor of prostate Uncertain:1
Uncertain significance, no assertion criteria providedliterature onlyScience for Life laboratory, Karolinska Institutet-- -
Breast neoplasm Other:1
not provided, no classification providedliterature onlyDatabase of Curated Mutations (DoCM)Mar 10, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.55
Cadd
Pathogenic
28
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.32
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
0.69
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
0.96
D
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-7.4
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0020
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
1.0
.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.
Vest4
0.95
MutPred
0.99
Loss of MoRF binding (P = 0.0762);.;.;.;.;.;.;.;Loss of MoRF binding (P = 0.0762);.;Loss of MoRF binding (P = 0.0762);Loss of MoRF binding (P = 0.0762);Loss of MoRF binding (P = 0.0762);.;.;Loss of MoRF binding (P = 0.0762);.;.;.;
MVP
1.0
MPC
0.44
ClinPred
0.99
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.92
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913343; hg19: chr17-7577121; COSMIC: COSV52662066; COSMIC: COSV52662066; API