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
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.817C>T | p.Arg273Cys | 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.817C>T | p.Arg273Cys | missense_variant | 8/11 | 1 | NM_000546.6 | ENSP00000269305 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152044Hom.: 0 Cov.: 31 FAILED QC
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250850Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135626
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461760Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727184
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152044Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74256
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jul 06, 2017 | This 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Feb 03, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 20, 2024 | This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7887414, 9047394, 10864200]. Functional studies indicate this variant impacts protein function [PMID: 8001119, 16861262, 9482117]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg 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, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 14, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 27, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 22, 2023 | Published 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 submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | TP53: PS3, PM1, PM2, PP4, PS4:Supporting - |
Li-Fraumeni syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2024 | This 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 10, 2020 | The p.Arg273Cys variant in TP53 has been reported in >5 individuals with Li-Fraumeni syndrome (LFS) or LFS-associated tumors (Gonzalez 2009, Janavicius 2011, Masciari 2011, Park 2016, Chan 2018). It has also been identified in 0.005% (1/21592) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 43594). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro and in vivo functional studies provide some evidence that this variant impacts/does not impact protein function (Thukral 1994, Kato 2003, Monti 2011, Li 2014) ; however, these types of assays may not accurately represent biological function. An additional variant involving this codon (p.Arg273Leu) has been identified in individuals with LFS and is classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP Criteria applied: PS4, PM5, PS3_Moderate, PM2_Supporting, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 08, 2023 | Variant 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2021 | The 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. - |
Neoplasm Pathogenic:1Other:1
-, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Ovarian neoplasm Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Acute myeloid leukemia Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Adrenocortical carcinoma, hereditary Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 01, 2024 | - - |
Multiple myeloma Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Biotechnology, Institute of Science, Nirma University | Mar 07, 2024 | The TP53 mutation takes place in the coding region of exon 8. This gene is one of the master components of the apoptotic cycle. The mutation does not lead to any structural change due to the absence of premature chain termination rather there is p. Arg273Cys substitution, which weakens the interaction of the TP53 to the Damaged DNA due to the weakening of the salt bridge, which could also lead to spoptotic disregulation. Hence, being classified as Pathogenic. - |
TP53-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 15, 2024 | The TP53 c.817C>T variant is predicted to result in the amino acid substitution p.Arg273Cys. This variant has been seen in at least 20 patients with TP53 related disease (Monti et al 2007. PubMed ID: 17606709; Gao F et al 2020. PubMed ID: 32817165; Masciari S et al 2011. PubMed ID: 21552135; Khincha PP et al 2019. PubMed ID: 31212162). This has been reported de novo in a patient with brain and breast cancers (Gao et al 2020.PubMed ID: 32817165). This variant has been shown to decrease protein function (Monti et al 2011. PubMed ID: 21343334). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/43594/). This variant is interpreted as pathogenic. - |
Hepatocellular carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Malignant tumor of prostate Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Science for Life laboratory, Karolinska Institutet | - | - - |
Breast neoplasm Other:1
not provided, no classification provided | literature only | Database of Curated Mutations (DoCM) | Mar 10, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at