rs397516436
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000546.6(TP53):c.637C>T(p.Arg213Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R213R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000546.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.637C>T | p.Arg213Ter | stop_gained | 6/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.637C>T | p.Arg213Ter | stop_gained | 6/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 152104Hom.: 0 Cov.: 33 FAILED QC
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461888Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152104Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74290
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 12, 2023 | _x000D_ Criteria applied: PVS1, PS4, PM2_SUP - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 15, 2024 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Li-Fraumeni syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Arg213*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 7887414, 11479205, 16401470, 16534790, 21552135, 21626334). ClinVar contains an entry for this variant (Variation ID: 43590). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 20, 2013 | The Arg213X variant in TP53 has been previously reported in the literature in se veral individuals with features consistent with or a clinical diagnosis of LFS ( Horio 1994, Frebourg 1995, Varley 1999, Vahteristo 2001, Wong 2006, Trahair 2007 , Ferrarini 2011). Varley et al. (1999) also observed loss of heterozygosity for TP53 in an adrenocortical carcinoma tumor from an individual with the germline Arg213X variant. This variant has been well described as a somatic variant in mu ltiple tumor types, including those found as part of LFS (COSMIC). The Arg213X v ariant leads to a premature stop at codon 213. From this DNA sequencing test, we cannot determine the effect this nucleotide change will have on the protein pro duced, but it is predicted to lead to a truncated or absent protein. Therefore, this variant is highly likely to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 03, 2023 | Variant summary: TP53 c.637C>T (p.Arg213X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251460 control chromosomes. c.637C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome and related conditions with co-segregation evidence (Example: Frebourg_1995, Trahair_2007, Masciari_2011 etc.). 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. A section of an NSCLC with the variant was negative for TP53 staining, suggesting the transcript is a target for nonsense mediated decay (Hashimoto_1999). Another report shows severe decrease in DNA binding (Malcikova_2010). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 18, 2022 | The p.R213* pathogenic mutation (also known as c.637C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 637. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has previously been reported in an affected individual from a family meeting classic Li-Fraumeni syndrome criteria (Wong P et al. Gastroenterology. 2006 Jan;130(1):73-9). This mutation has also been reported in patients with gastric cancer, breast cancer and medulloblastoma (Horio Y et al. Oncogene. 1994 Apr;9(4):1231-5; Momota H et al. Pediatr. Blood Cancer. 2010 Sep;55(3):577-9; Masciari S et al. Genet. Med. 2011 Jul;13(7):651-7; Rummel SK et al. Breast Cancer Res. Treat. 2017 Aug;164(3):593-601; Waszak SM et al. Lancet Oncol. 2018 Jun;19(6):785-798). In addition this mutation was shown to result in loss of DNA binding compared to wild-type (Malcikova J et al. Biol. Chem. 2010 Feb-Mar;391(2-3):197-205). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of DNA binding and growth suppression activities (Malcikova 2010, Kotler 2018); Not observed at significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 11479205, 25525159, 15656799, 24803582, 30309854, 10486318, 28056804, 29655027, 27059324, 29489754, 20128691, 8134126, 21552135, 20658636, 21626334, 22203015, 15099937, 7887414, 16401470, 24220311, 23334668, 24702488, 26681312, 15902285, 28503720, 29351612, 29979965, 30412573, 29354595, 29700339, 29076966, 21225465, 27146902, 26425688, 9667734, 20522432, 29753700, 30720243, 31278746, 27535533, 31105275, 32000721, 30816478) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 18, 2022 | This nonsense variant causes the premature termination of TP53 protein synthesis. It 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 with Li Fraumeni Syndrome (PMID: 21552135 (2011)), colorectal cancer (PMID: 26425688 (2015), 32000721 (2020)), breast cancer (PMID: 32994724 (2020), 28503720 (2017), 26681312 (2015)), and ovarian cancer (PMID: 27059324 (2016)). The variant has also been reported in individuals with glioma (PMID: 31278746 (2019)) and medulloblastoma (PMID: 29753700 (2018), 29489754 (2018). Based on the available information, this variant is classified as pathogenic. - |
Familial cancer of breast Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | University Health Network, Princess Margaret Cancer Centre | Mar 19, 2021 | - - |
Pathogenic, criteria provided, single submitter | case-control | Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo | - | - - |
Colorectal cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | case-control | Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo | - | - - |
Ovarian neoplasm Pathogenic:1
Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Squamous cell carcinoma of the head and neck Pathogenic:1
Pathogenic, criteria provided, single submitter | case-control | Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at