rs730882029
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000546.6(TP53):c.1024C>T(p.Arg342Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R342R) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
TP53
NM_000546.6 stop_gained
NM_000546.6 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 1.17
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 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-7670685-G-A is Pathogenic according to our data. Variant chr17-7670685-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 182970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7670685-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| TP53 | NM_000546.6 | c.1024C>T | p.Arg342Ter | stop_gained | 10/11 | ENST00000269305.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TP53 | ENST00000269305.9 | c.1024C>T | p.Arg342Ter | stop_gained | 10/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:19
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Mar 31, 2022 | PVS1, PM1, PM2_SUP - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2022 | 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; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19714490, 28693246, 34249677, 35016432, 24382691, 26425688, 21761402, 20436704, 10519380, 12779080, 18555592, 9115587, 21190917, 16969106, 12509970, 21665182, 28408749, 23484829, 17567834, 28526081, 18511570, 19556618, 26911350, 19711436, 30720243, 31081129, 31105275, 31447099, 32817165, 31742824, 33294277) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 06, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Feb 02, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 18, 2018 | The TP53 c.1024C>T; p.Arg342Ter variant (rs730882029) is reported in the germline of at least two individuals with suspected Li Fraumeni syndrome (Hettmer 2014, Trkova 2007). The variant is listed as pathogenic by several sources in the ClinVar database (Variation ID: 182970), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is classified as pathogenic. References: Hettmer S et al. Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer. 2014 Apr 1;120(7):1068-75. Trkova M et al. Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. Cancer. 2007 Aug 1;110(3):694-702. - |
Hereditary cancer-predisposing syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 11, 2021 | This variant changes 1 nucleotide in exon 10 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown the mutant protein to be mis-localized and unable to activate downstream targets (PMID: 16969106). This variant has been reported in multiple individuals affected with Li-Fraumeni syndrome-associated cancer, including childhood onset adrenocarcinoma, brain tumor and soft-tissue sarcoma (PMID: 17567834, 19711436, 19714490, 19556618, 24382691) and adult-onset breast and/or ovarian cancer (PMID: 21761402, 26911350). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2022 | The p.R342* pathogenic mutation (also known as c.1024C>T), located in coding exon 9 of the TP53 gene, results from a C to T substitution at nucleotide position 1024. This changes the amino acid from an arginine to a stop codon within coding exon 9. In one study, this mutation was detected in a 5-year-old male diagnosed with an adrenocortical tumor at 1.5 years of age and a medulloblastoma at 5 years of age. His 31-year-old unaffected father was also a carrier of the mutation (Trkova et al. Cancer. 2007 Aug;110(3):694-702). In another study, this alteration was identified in a 4-year-old who had been diagnosed with osteosarcoma, adenocarcinoma, and anaplastic rhabdomyosarcoma (Hettmer S et al. Cancer 2014 Apr;120(7):1068-75). It has also been reported in patients and/or families with breast and/or ovarian cancer (Melhem-Bertrandt A et al. Cancer 2012 Feb;118:908-13; Mannan AU et al. J. Hum. Genet. 2016 Jun;61:515-22; Shao D et al. Cancer Sci, 2020 Feb;111:647-657). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 10, 2022 | - - |
Li-Fraumeni syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 06, 2024 | This sequence change creates a premature translational stop signal (p.Arg342*) 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: 17567834, 19714490, 21761402, 24382691, 26911350). ClinVar contains an entry for this variant (Variation ID: 182970). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 25, 2024 | Variant summary: TP53 c.1024C>T (p.Arg342X) 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. The variant was absent in 251350 control chromosomes (gnomAD) but has been reported in the literature in multiple individuals affected with features of Li-Fraunemia syndrome such as breast and/or ovarian cancer, osteosarcoma, adenocarcinoma, adrenocortical carcinoma, foot fibrosarcoma and prostate cancer (Mannan_2016, Hettmer_2014, Fiszer-Maliszewska_2009, Wang_2013). These data indicate that the variant is very likely to be associated with disease. An experimental study using a cell system reports that this truncation impaired association with dynein motor complex and prevented p53 nuclear translocation (Trostel_2006). However, this does not allow convincing conclusions about the variant effect. 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 20, 2018 | The p.Arg342X variant in TP53 has been reported as a germline variant in more th an 15 individuals with TP53-associated cancers and as a somatic variant in more than 100 individuals (Fiszer-Maliszewska 2009, Schniederjan 2009, Lee 2010, Melh em-Bertrandt 2012, Hettmer 2014, Kandioler 2015, Mannan 2016, Smardova 2016, IAR C TP53 database [http://p53.iarc.fr/], COSMIC database). This variant has also b een reported in ClinVar (Variation ID# 182970) and was absent from large populat ion studies. In vitro functional studies provide some evidence that the p.Arg342 X variant may impact protein function by resulting in abnormal nuclear localizat ion (Trostel 2006). This nonsense variant leads to a premature termination codon at position 342 which is predicted to lead to a truncated or absent protein. He terozygous loss of function of the TP53 gene is an established disease mechanism in Li-Fraumeni syndrome. In summary, this variant meets criteria to be classifi ed as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner based upon frequency in affected individuals, absence from controls, and the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1; PS4; PM2; PS3_Supportin g. - |
Li-Fraumeni syndrome 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 21, 2024 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Adrenocortical carcinoma, hereditary Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 28, 2022 | - - |
Colonic diverticula Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 09, 2021 | - - |
Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;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;C4748488:Bone marrow failure syndrome 5 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 14, 2021 | - - |
Gallbladder cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Institute of Medical Sciences, Banaras Hindu University | Oct 30, 2020 | - - |
Ovarian neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A;N;N;N;N
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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