The TP53 c.586C>T, p.Arg196Ter variant (rs397516435) has been reported in multiple individuals diagnosed with Li-Fraumeni syndrome (Bendig 2004, Grayson 1994, Vahteristo 2001, Villani 2016). It is observed in the Genome Aggregation Database general population database at a frequency of 0.00041 percent. The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Bendig I et al. Identification of novel TP53 mutations in familial and sporadic cancer cases of German and Swiss origin. Cancer Genet Cytogenet. 2004; 154(1):22-6. Grayson G et al. Novel germline mutation of the p53 tumor suppressor gene in a child with incidentally discovered adrenal cortical carcinoma. Am J Pediatr Hematol Oncol. 1994; 16(4):341-7. Vahteristo P et al. p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 2001; 61(15):5718-22. Villani A et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016; 17(9):1295-305.
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.586C>T (p.Arg196Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(20)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
20
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.586C>T (p.Arg196Ter)
Variation ID: 43589 Accession: VCV000043589.47
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.1 17: 7674945 (GRCh38) [ NCBI UCSC ] 17: 7578263 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 1, 2016 Sep 8, 2024 Aug 16, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.586C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg196Ter nonsense NM_001126112.3:c.586C>T NP_001119584.1:p.Arg196Ter nonsense NM_001126113.3:c.586C>T NP_001119585.1:p.Arg196Ter nonsense NM_001126114.3:c.586C>T NP_001119586.1:p.Arg196Ter nonsense NM_001126115.2:c.190C>T NP_001119587.1:p.Arg64Ter nonsense NM_001126116.2:c.190C>T NP_001119588.1:p.Arg64Ter nonsense NM_001126117.2:c.190C>T NP_001119589.1:p.Arg64Ter nonsense NM_001126118.2:c.469C>T NP_001119590.1:p.Arg157Ter nonsense NM_001276695.3:c.469C>T NP_001263624.1:p.Arg157Ter nonsense NM_001276696.3:c.469C>T NP_001263625.1:p.Arg157Ter nonsense NM_001276697.3:c.109C>T NP_001263626.1:p.Arg37Ter nonsense NM_001276698.3:c.109C>T NP_001263627.1:p.Arg37Ter nonsense NM_001276699.3:c.109C>T NP_001263628.1:p.Arg37Ter nonsense NM_001276760.3:c.469C>T NP_001263689.1:p.Arg157Ter nonsense NM_001276761.3:c.469C>T NP_001263690.1:p.Arg157Ter nonsense NC_000017.11:g.7674945G>A NC_000017.10:g.7578263G>A NG_017013.2:g.17606C>T LRG_321:g.17606C>T LRG_321t1:c.586C>T LRG_321p1:p.Arg196Ter - Protein change
- R157*, R196*, R64*, R37*
- Other names
- p.Arg196Ter
- Canonical SPDI
- NC_000017.11:7674944:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3364 | 3463 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 18, 2022 | RCV000131510.18 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2024 | RCV000205265.30 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Nov 9, 2022 | RCV000412710.27 | |
| Pathogenic (1) |
no assertion criteria provided
|
Dec 1, 2018 | RCV000785329.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 19, 2021 | RCV001527464.9 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 16, 2024 | RCV002288535.10 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 11, 2024 | RCV003473274.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 26, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000597519.1
First in ClinVar: Jul 01, 2016 Last updated: Jul 01, 2016 |
|
|
|
Pathogenic
(Jan 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Adrenocortical carcinoma, hereditary
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004204262.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(May 10, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605426.2
First in ClinVar: Sep 30, 2017 Last updated: Feb 17, 2019 |
Comment:
The TP53 c.586C>T, p.Arg196Ter variant (rs397516435) has been reported in multiple individuals diagnosed with Li-Fraumeni syndrome (Bendig 2004, Grayson 1994, Vahteristo 2001, Villani 2016). It … (more)
The TP53 c.586C>T, p.Arg196Ter variant (rs397516435) has been reported in multiple individuals diagnosed with Li-Fraumeni syndrome (Bendig 2004, Grayson 1994, Vahteristo 2001, Villani 2016). It is observed in the Genome Aggregation Database general population database at a frequency of 0.00041 percent. The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Bendig I et al. Identification of novel TP53 mutations in familial and sporadic cancer cases of German and Swiss origin. Cancer Genet Cytogenet. 2004; 154(1):22-6. Grayson G et al. Novel germline mutation of the p53 tumor suppressor gene in a child with incidentally discovered adrenal cortical carcinoma. Am J Pediatr Hematol Oncol. 1994; 16(4):341-7. Vahteristo P et al. p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 2001; 61(15):5718-22. Villani A et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016; 17(9):1295-305. (less)
|
|
|
Pathogenic
(Mar 30, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000060186.6
First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019 |
Comment:
The p.Arg196X variant in TP53 has been reported in >10 individuals with Li-Fraum eni syndrome, with a de novo occurrence in at least 1 individual, … (more)
The p.Arg196X variant in TP53 has been reported in >10 individuals with Li-Fraum eni syndrome, with a de novo occurrence in at least 1 individual, and segregated with disease in 1 affected relative from 1 family (Grayson 1994, Vahteristo 200 1, Bendig 2004, Trkova 2007, Pinto 2009, Masciari 2011, Mitchell 2013, Meric-Ber nstam 2016, Villani 2016, LMM data). It has also been identified in 1/111706 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs397516435); however this frequency is low enough to be consistent with the frequency of Li-Fraumeni syndrome in the general population. This nonsense variant leads to a premature termination codon at position 196, w hich is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TP53 gene is an established disease mechanism in individuals wi th Li-Fraumeni syndrome. In summary, this variant meets criteria to be classifie d as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner. ACMG/A MP criteria applied: PVS1, PM2, PM6. (less)
Number of individuals with the variant: 2
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
de novo
|
Department of Pediatric Oncology, Hematology and Clinical Immunology, University Clinics Duesseldorf
Accession: SCV001482285.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Family history: no
|
|
|
Pathogenic
(Dec 08, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001351214.2
First in ClinVar: Jun 22, 2020 Last updated: Jun 19, 2021 |
Comment:
This variant changes 1 nucleotide in exon 6 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in … (more)
This variant changes 1 nucleotide in exon 6 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 11479205, 19468865), suspected Li-Fraumeni syndrome (PMID: 28573494), childhood adrenal cortical carcinoma (PMID: 7978053) and adult-onset sarcoma (PMID 23894400). This variant has also been observed de novo in an individual affected with rhabdomyosarcoma (PMID: 15381368) This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134872.3
First in ClinVar: Jan 04, 2020 Last updated: Jan 01, 2022 |
Comment:
The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and … (more)
The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. (less)
|
|
|
Pathogenic
(Jun 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002582485.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
|
Pathogenic
(Jun 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002583146.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
|
Pathogenic
(Nov 09, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000490858.3
First in ClinVar: Jan 09, 2017 Last updated: May 06, 2023 |
Comment:
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 … (more)
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: decreased DNA binding and transactivation of p53 targets, loss of growth suppression activity (Malcikova 2010, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25757876, 10519380, 24696321, 22187033, 26787237, 28573494, 32504368, 33840814, 29922827, 34282142, 31721094, 17567834, 21761402, 21552135, 23894400, 20128691, 20805372, 25617798, 26425688, 25773284, 25412846, 11479205, 15381368, 19468865, 23580068, 18555592, 8080050, 10226610, 10567903, 12124823, 16322298, 27226433, 28091804, 27501770, 28177947, 29076966, 29979965, 29489754, 30709875, 30268473, 28991257, 30720243, 30730459, 7978053, 31105275, 30982232, 32817165, 31958074, 32368696, 33084842, 33674644, 34863587, 35974385, 35441217, 35418818, 25525159) (less)
|
|
|
Pathogenic
(Feb 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004932444.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
|
|
|
Pathogenic
(Mar 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186503.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.R196* pathogenic mutation (also known as c.586C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at … (more)
The p.R196* pathogenic mutation (also known as c.586C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 586. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been reported in a number of individuals with early onset or multiple cancers and in some families who meet either classic diagnostic criteria or Chompret criteria for Li-Fraumeni syndrome (LFS) (Vahteristo P et al. Cancer Research. 2001 Aug;61:5718-5722; Pinto C et al. Fam. Cancer 2009 May;8:383-90; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Mitchell G et al. PLoS One. 2013 Jul;8(7):e69026; Villani A et al. Lancet Oncol. 2016 Sep;17:1295-305; Saya S et al. Fam Cancer. 2017 Jul;16(3):433-440). 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. (less)
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447028.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Sex: female
|
|
|
Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011369.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
|
Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000260299.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg196*) in the TP53 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg196*) 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 present in population databases (rs397516435, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 7978053, 11479205, 15381368, 19468865, 21552135, 23894400). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43589). 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. (less)
|
|
|
Pathogenic
(Aug 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
germline
|
Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili
Accession: SCV005200616.1
First in ClinVar: Sep 08, 2024 Last updated: Sep 08, 2024 |
Number of individuals with the variant: 1
Age: 30-39 years
Sex: female
Ethnicity/Population group: Latin
Geographic origin: Colombia
|
|
|
Pathogenic
(Mar 19, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Not specified
No history of cancer or disease
(more...)
Affected status: no
Allele origin:
somatic
|
University Health Network, Princess Margaret Cancer Centre
Accession: SCV001738479.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021 |
Secondary finding: yes
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001957804.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(Dec 01, 2018)
|
no assertion criteria provided
Method: research
|
Ovarian neoplasm
Affected status: yes
Allele origin:
somatic
|
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000923897.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001905932.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Comment:
Comment:
The p.Arg196X variant in TP53 has been reported in >10 individuals with Li-Fraum eni syndrome, with a de novo occurrence in at least 1 individual, and segregated with disease in 1 affected relative from 1 family (Grayson 1994, Vahteristo 200 1, Bendig 2004, Trkova 2007, Pinto 2009, Masciari 2011, Mitchell 2013, Meric-Ber nstam 2016, Villani 2016, LMM data). It has also been identified in 1/111706 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs397516435); however this frequency is low enough to be consistent with the frequency of Li-Fraumeni syndrome in the general population. This nonsense variant leads to a premature termination codon at position 196, w hich is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TP53 gene is an established disease mechanism in individuals wi th Li-Fraumeni syndrome. In summary, this variant meets criteria to be classifie d as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner. ACMG/A MP criteria applied: PVS1, PM2, PM6.
Comment:
This variant changes 1 nucleotide in exon 6 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 11479205, 19468865), suspected Li-Fraumeni syndrome (PMID: 28573494), childhood adrenal cortical carcinoma (PMID: 7978053) and adult-onset sarcoma (PMID 23894400). This variant has also been observed de novo in an individual affected with rhabdomyosarcoma (PMID: 15381368) This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Comment:
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: decreased DNA binding and transactivation of p53 targets, loss of growth suppression activity (Malcikova 2010, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25757876, 10519380, 24696321, 22187033, 26787237, 28573494, 32504368, 33840814, 29922827, 34282142, 31721094, 17567834, 21761402, 21552135, 23894400, 20128691, 20805372, 25617798, 26425688, 25773284, 25412846, 11479205, 15381368, 19468865, 23580068, 18555592, 8080050, 10226610, 10567903, 12124823, 16322298, 27226433, 28091804, 27501770, 28177947, 29076966, 29979965, 29489754, 30709875, 30268473, 28991257, 30720243, 30730459, 7978053, 31105275, 30982232, 32817165, 31958074, 32368696, 33084842, 33674644, 34863587, 35974385, 35441217, 35418818, 25525159)
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
The p.R196* pathogenic mutation (also known as c.586C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 586. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been reported in a number of individuals with early onset or multiple cancers and in some families who meet either classic diagnostic criteria or Chompret criteria for Li-Fraumeni syndrome (LFS) (Vahteristo P et al. Cancer Research. 2001 Aug;61:5718-5722; Pinto C et al. Fam. Cancer 2009 May;8:383-90; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Mitchell G et al. PLoS One. 2013 Jul;8(7):e69026; Villani A et al. Lancet Oncol. 2016 Sep;17:1295-305; Saya S et al. Fam Cancer. 2017 Jul;16(3):433-440). 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.
Comment:
This sequence change creates a premature translational stop signal (p.Arg196*) 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 present in population databases (rs397516435, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 7978053, 11479205, 15381368, 19468865, 21552135, 23894400). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43589). 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.
Comment on condition
No history of cancer or disease reported in this indivudal
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The TP53 c.586C>T, p.Arg196Ter variant (rs397516435) has been reported in multiple individuals diagnosed with Li-Fraumeni syndrome (Bendig 2004, Grayson 1994, Vahteristo 2001, Villani 2016). It is observed in the Genome Aggregation Database general population database at a frequency of 0.00041 percent. The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Bendig I et al. Identification of novel TP53 mutations in familial and sporadic cancer cases of German and Swiss origin. Cancer Genet Cytogenet. 2004; 154(1):22-6. Grayson G et al. Novel germline mutation of the p53 tumor suppressor gene in a child with incidentally discovered adrenal cortical carcinoma. Am J Pediatr Hematol Oncol. 1994; 16(4):341-7. Vahteristo P et al. p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 2001; 61(15):5718-22. Villani A et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016; 17(9):1295-305.
Comment:
The p.Arg196X variant in TP53 has been reported in >10 individuals with Li-Fraum eni syndrome, with a de novo occurrence in at least 1 individual, and segregated with disease in 1 affected relative from 1 family (Grayson 1994, Vahteristo 200 1, Bendig 2004, Trkova 2007, Pinto 2009, Masciari 2011, Mitchell 2013, Meric-Ber nstam 2016, Villani 2016, LMM data). It has also been identified in 1/111706 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs397516435); however this frequency is low enough to be consistent with the frequency of Li-Fraumeni syndrome in the general population. This nonsense variant leads to a premature termination codon at position 196, w hich is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TP53 gene is an established disease mechanism in individuals wi th Li-Fraumeni syndrome. In summary, this variant meets criteria to be classifie d as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner. ACMG/A MP criteria applied: PVS1, PM2, PM6.
Comment:
This variant changes 1 nucleotide in exon 6 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 11479205, 19468865), suspected Li-Fraumeni syndrome (PMID: 28573494), childhood adrenal cortical carcinoma (PMID: 7978053) and adult-onset sarcoma (PMID 23894400). This variant has also been observed de novo in an individual affected with rhabdomyosarcoma (PMID: 15381368) This variant has been identified in 1/251474 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Comment:
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: decreased DNA binding and transactivation of p53 targets, loss of growth suppression activity (Malcikova 2010, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25757876, 10519380, 24696321, 22187033, 26787237, 28573494, 32504368, 33840814, 29922827, 34282142, 31721094, 17567834, 21761402, 21552135, 23894400, 20128691, 20805372, 25617798, 26425688, 25773284, 25412846, 11479205, 15381368, 19468865, 23580068, 18555592, 8080050, 10226610, 10567903, 12124823, 16322298, 27226433, 28091804, 27501770, 28177947, 29076966, 29979965, 29489754, 30709875, 30268473, 28991257, 30720243, 30730459, 7978053, 31105275, 30982232, 32817165, 31958074, 32368696, 33084842, 33674644, 34863587, 35974385, 35441217, 35418818, 25525159)
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
The p.R196* pathogenic mutation (also known as c.586C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 586. This changes the amino acid from an arginine to a stop codon within coding exon 5. This mutation has been reported in a number of individuals with early onset or multiple cancers and in some families who meet either classic diagnostic criteria or Chompret criteria for Li-Fraumeni syndrome (LFS) (Vahteristo P et al. Cancer Research. 2001 Aug;61:5718-5722; Pinto C et al. Fam. Cancer 2009 May;8:383-90; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Mitchell G et al. PLoS One. 2013 Jul;8(7):e69026; Villani A et al. Lancet Oncol. 2016 Sep;17:1295-305; Saya S et al. Fam Cancer. 2017 Jul;16(3):433-440). 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.
Comment:
This sequence change creates a premature translational stop signal (p.Arg196*) 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 present in population databases (rs397516435, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 7978053, 11479205, 15381368, 19468865, 21552135, 23894400). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43589). 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.
Comment on condition
No history of cancer or disease reported in this indivudal
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Hematologic malignancies and Li-Fraumeni syndrome. | Swaminathan M | Cold Spring Harbor molecular case studies | 2019 | PMID: 30709875 |
| The landscape of genomic alterations across childhood cancers. | Gröbner SN | Nature | 2018 | PMID: 29489754 |
| A novel TP53 germline inframe deletion identified in a Spanish series of Li-fraumeni syndrome suspected families. | Llovet P | Familial cancer | 2017 | PMID: 28573494 |
| Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls. | Saya S | Familial cancer | 2017 | PMID: 28091804 |
| Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. | Villani A | The Lancet. Oncology | 2016 | PMID: 27501770 |
| Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol. | Meric-Bernstam F | Annals of oncology : official journal of the European Society for Medical Oncology | 2016 | PMID: 26787237 |
| Tumor genome analysis includes germline genome: are we ready for surprises? | Catenacci DV | International journal of cancer | 2015 | PMID: 25123297 |
| High frequency of germline TP53 mutations in a prospective adult-onset sarcoma cohort. | Mitchell G | PloS one | 2013 | PMID: 23894400 |
| Prevalence of germline TP53 mutations in HER2+ breast cancer patients. | Rath MG | Breast cancer research and treatment | 2013 | PMID: 23580068 |
| Early onset HER2-positive breast cancer is associated with germline TP53 mutations. | Melhem-Bertrandt A | Cancer | 2012 | PMID: 21761402 |
| Gastric cancer in individuals with Li-Fraumeni syndrome. | Masciari S | Genetics in medicine : official journal of the American College of Medical Genetics | 2011 | PMID: 21552135 |
| TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. | Ruijs MW | Journal of medical genetics | 2010 | PMID: 20522432 |
| Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. | Malcikova J | Biological chemistry | 2010 | PMID: 20128691 |
| TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset. | Pinto C | Familial cancer | 2009 | PMID: 19468865 |
| Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. | Trkova M | Cancer | 2007 | PMID: 17567834 |
| Identification of novel TP53 mutations in familial and sporadic cancer cases of German and Swiss origin. | Bendig I | Cancer genetics and cytogenetics | 2004 | PMID: 15381368 |
| p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. | Vahteristo P | Cancer research | 2001 | PMID: 11479205 |
| Novel germline mutation of the p53 tumor suppressor gene in a child with incidentally discovered adrenal cortical carcinoma. | Grayson GH | The American journal of pediatric hematology/oncology | 1994 | PMID: 7978053 |
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Text-mined citations for rs397516435 ...
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Record last updated Oct 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.