proposed classification - variant undergoing re-assessment, contact laboratory
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.473G>A (p.Arg158His)
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.
(25)
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/Likely pathogenic
25
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.473G>A (p.Arg158His)
Variation ID: 141963 Accession: VCV000141963.48
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7675139 (GRCh38) [ NCBI UCSC ] 17: 7578457 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Aug 7, 2017 Sep 16, 2024 Jun 7, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.473G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg158His missense NM_001126112.3:c.473G>A NP_001119584.1:p.Arg158His missense NM_001126113.3:c.473G>A NP_001119585.1:p.Arg158His missense NM_001126114.3:c.473G>A NP_001119586.1:p.Arg158His missense NM_001126115.2:c.77G>A NP_001119587.1:p.Arg26His missense NM_001126116.2:c.77G>A NP_001119588.1:p.Arg26His missense NM_001126117.2:c.77G>A NP_001119589.1:p.Arg26His missense NM_001126118.2:c.356G>A NP_001119590.1:p.Arg119His missense NM_001276695.3:c.356G>A NP_001263624.1:p.Arg119His missense NM_001276696.3:c.356G>A NP_001263625.1:p.Arg119His missense NM_001276697.3:c.-5G>A 5 prime UTR NM_001276698.3:c.-5G>A 5 prime UTR NM_001276699.3:c.-5G>A 5 prime UTR NM_001276760.3:c.356G>A NP_001263689.1:p.Arg119His missense NM_001276761.3:c.356G>A NP_001263690.1:p.Arg119His missense NC_000017.11:g.7675139C>T NC_000017.10:g.7578457C>T NG_017013.2:g.17412G>A LRG_321:g.17412G>A LRG_321t1:c.473G>A LRG_321p1:p.Arg158His LRG_321t2:c.473G>A LRG_321:p.Arg158His P04637:p.Arg158His - Protein change
- R119H, R158H, R26H
- Other names
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- Canonical SPDI
- NC_000017.11:7675138:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
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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.
- -
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
- Links
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 |
3367 | 3466 | |
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/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
May 11, 2023 | RCV000130708.23 | |
| Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 19, 2024 | RCV000227859.28 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Jun 7, 2024 | RCV000255654.32 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 1, 2020 | RCV001257522.9 | |
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Feb 14, 2024 | RCV000496787.13 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 23, 2022 | RCV003492603.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 24, 2023 | RCV003461996.1 |
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. |
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|---|---|---|---|---|---|
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Pathogenic
(Dec 10, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
UCLA Clinical Genomics Center, UCLA
Study: CES
Accession: SCV000588155.1 First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017 |
Age: 40-49 years
Sex: male
Ethnicity/Population group: European Caucasian
Testing laboratory: UCLA Clinical Genomics Center
|
|
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Likely pathogenic
(Nov 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785720.2
First in ClinVar: Aug 07, 2017 Last updated: Aug 07, 2017 |
|
|
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Pathogenic
(Feb 13, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000713289.3
First in ClinVar: Apr 09, 2018 Last updated: Jul 03, 2020 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 1
|
|
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Pathogenic
(Sep 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579128.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3, PS4_MOD, PM5, PM2_SUP, PP1, PP3
|
Number of individuals with the variant: 3
Sex: female
|
|
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Likely 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: SCV002582392.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
|
Likely 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: SCV002583053.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
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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: SCV002011371.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
LI-FRAUMENI SYNDROME
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046280.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported as a heterozygous change in patients with TP53-related cancers and Li-Fraumeni syndrome (PMID: 10486318, 23894400, 20455025, 24764719, 26014290, 23175693, … (more)
This variant has been previously reported as a heterozygous change in patients with TP53-related cancers and Li-Fraumeni syndrome (PMID: 10486318, 23894400, 20455025, 24764719, 26014290, 23175693, 20522432, 17606709, 21601526, 18685109). Experimental studies have shown that this variant affects TP53 function (PMID: 10229196, 12826609, 25584008, 21343334). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (1/251268) and thus is presumed to be rare. The c.473G>A (p.Arg158His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.473G>A (p.Arg158His) variant is classified as Pathogenic. (less)
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Pathogenic
(May 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Adrenocortical carcinoma, hereditary
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004206277.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
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Pathogenic
(Jan 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004221359.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000099 (1/10070 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000099 (1/10070 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Li Fraumeni Syndrome (LFS), breast cancer, acute myeloid leukemia, and Li Fraumeni Syndrome associated cancers (PMIDs: 33372952 (2020), 32427313 (2020), 31105275 (2019), 31081129 (2019), 27501770 (2016), 26014290 (2015), 23894400 (2013), 22186996 (2012), 21761402 (2012), 21601526 (2011), 21464421 (2011)). Published functional studies have reported that this variant results in a damaging affect on TP53 protein function (PMIDs: 28472496 (2017), 25584008 (2015), 20522432 (2010), IARC TP53 https://p53.iarc.fr/). Based on the available information, this variant is classified as pathogenic. (less)
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Likely pathogenic
(Dec 23, 2022)
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criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239786.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Jan 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000285199.11
First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). This variant is present in population databases (rs587782144, gnomAD 0.01%). This missense change has been observed in individuals with TP53-related cancers (PMID: 10486318, 17606709, 18685109, 20455025, 20522432, 21601526, 23175693, 23894400, 24764719, 26014290). It has also been observed to segregate with disease in related individuals. This variant is also known as c.12407G>A. ClinVar contains an entry for this variant (Variation ID: 141963). 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: 10229196, 12826609, 21343334, 25584008). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Likely pathogenic
(Feb 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004933726.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21464421, 17308077]. This variant … (more)
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21464421, 17308077]. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 10229196]. (less)
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|
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Pathogenic
(Feb 11, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185595.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.R158H pathogenic mutation (also known as c.473G>A) is located in coding exon 4 of the TP53 gene. This alteration results from a G to … (more)
The p.R158H pathogenic mutation (also known as c.473G>A) is located in coding exon 4 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 473. The arginine at codon 158 is replaced by histidine, an amino acid with some highly similar properties. This alteration has been reported in multiple individuals with clinical histories suspicious for Li-Fraumeni syndrome, with ages of onset ranging from childhood to adulthood (Varley JM et al. Am J Hum Genet. 1999; 65:995-1006; Villani A et al. Lancet Oncol. 2011 Jun;12(6):559-67; Mitchell G et al. PLoS One. 2013 Jul 22;8(7):e69026; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8; Bougeard GJ et al. J Med Genet. 2008 Aug;45(8):535-8; Wasserman JD et al. J. Clin. Oncol. 2015 Feb;33:602-9; Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812; Stjepanovic N et al. BMC Med Genomics. 2018 Aug;11(1):65). In a study of 214 French families with Li-Fraumeni syndrome, this alteration was identified in eight families; six of these families had cases of adrenocortical carcinoma (Bougeard G et al. J. Clin. Oncol., 2015 Jul;33:2345-52). This alteration is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based studies (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). 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). In addition, a recent functional study demonstrated that the reduction in transcriptional activity and DNA binding resulting from this amino acid substitution is similar to that observed in null mutations (Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812). Furthermore, three different TP53 missense mutations at the same codon have been reported to be associated with Li-Fraumeni syndrome: p.R158G, p.R158P, and p.R158C (Chompret A et al. Br J Cancer. 2000; 82(12):1932-7; Morgan JE et al. Hum Mutat. 2010;31(4):484-91; Herrmann LJ et al. J Clin Endocrinol Metab. 2012 Mar;97(3):E476-85). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Jun 07, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322153.12
First in ClinVar: Oct 09, 2016 Last updated: Sep 16, 2024 |
Comment:
Published functional studies demonstrate partial to non-functional transactivation, intermediate levels of growth suppression and colony reduction (PMID: 29979965, 11429705, 12826609, 21343334, 25584008, 10229196); Observed in … (more)
Published functional studies demonstrate partial to non-functional transactivation, intermediate levels of growth suppression and colony reduction (PMID: 29979965, 11429705, 12826609, 21343334, 25584008, 10229196); Observed in a few individuals not meeting classic Li-Fraumeni syndrome criteria but several with adrenocortical carcinoma (ACC), leading some authors to suggest this variant might cause reduced penetrance or later onset of tumors other than ACC similar to the TP53 Arg337His Brazilian founder variant (PMID: 26014290, 20455025, 21464421); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20308654, 14559903, 9738975, 21665242, 24590827, 22768918, 27343442, 24764719, 12826609, 26786923, 16494995, 17311302, 21761402, 23894400, 27619989, 18511570, 25584008, 11896595, 9115587, 9399658, 10519380, 12917626, 20522432, 20455025, 21343334, 21464421, 20593220, 21552135, 21601526, 23117049, 25773284, 24829203, 24868540, 24198462, 19671995, 26014290, 23175693, 10486318, 10229196, 28369373, 27501770, 27157322, 28408749, 18685109, 29085664, 28749946, 28466600, 28922847, 28597078, 29058986, 27844328, 25234657, 22170717, 21339461, 10864200, 28349240, 27328919, 25741868, 29755662, 29707145, 28887601, 28724667, 17606709, 11429705, 17308077, 29300620, 29979965, 31016814, 30840781, 31081129, 30092803, 30224644, 31494577, 31447099, 30720243, 31105275, 32427313, 32817165, 33372952, 34240179, 31721094, 33858029, 34308104, 34863587, 35974385, 35418818, 34273903, 35988656, 36495689, 37461096, 12909720, 28472496, 15510160, 37179382) (less)
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|
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Pathogenic
(Aug 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434921.1
First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
Comment:
The c.473G>A (p.Arg158His) variant in the TP53 gene has been reported in mulitple patients/families with cancers (PMID 10486318, 17308077, 20522432, 21552135, 21761402, 23175693, 23894400 and … (more)
The c.473G>A (p.Arg158His) variant in the TP53 gene has been reported in mulitple patients/families with cancers (PMID 10486318, 17308077, 20522432, 21552135, 21761402, 23175693, 23894400 and 24764719). This variant is observed with a low minor allele frequency in the gnomAD database (1/246110). This variant is at a mutation hotspot of the DNA binding domain where other pathogenic variants in the nearby region have been reported. Functional studies demonstrated decrease P53 functionality (PMID 17606709, 21343334 and 28472496). Therefore, the c.473G>A (p.Arg158His) variant in the TP53 gene is classified as pathogenic. (less)
|
|
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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: SCV001448119.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Breast carcinoma (present) , Leiomyosarcoma (present)
Sex: female
|
|
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Pathogenic
(Oct 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001360868.2
First in ClinVar: Jun 22, 2020 Last updated: Nov 19, 2022 |
Comment:
Variant summary: TP53 c.473G>A (p.Arg158His) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of … (more)
Variant summary: TP53 c.473G>A (p.Arg158His) 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 4e-06 in 251268 control chromosomes.c.473G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (LFS) or LFS spectrum tumors (e.g. Varley_1999, Bougeard_2008, Ceelen_2011); and at least one of these reports described co-segregation of the variant with Li-Fraumeni Syndrome in one family (Ceelen_2011). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function and demonstrated reduced overall transcription activity (TA) on several different promoters (e.g. Monti_2011, Wasserman_2015). Ten 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/likely pathogenic. Several different missense changes involving this codon (p.Arg158Leu, p.Arg158Gly, p.Arg158Cys, Arg158Pro) have been reported in individuals with TP53-related conditions (HGMD), indicating that this amino acid is important for TP53 function. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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|
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Pathogenic
(Jul 07, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
unknown
|
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Accession: SCV004015237.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). This variant is not observed at significant frequency in large population cohorts (gnomAD) . This missense change has been observed in individuals with TP53-related cancers (PMID: 10486318, 17606709, 18685109, 20455025, 20522432, 21601526, 23175693, 23894400, 24764719, 26014290). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 141963). In silico analysis supports that this missense variant has a deleterious effect on protein structure/function. Also,advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, aminoacid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TP53 protein function. (PMID: 10229196, 12826609, 21343334, 25584008). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(May 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000537627.6
First in ClinVar: Sep 24, 2016 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 158 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant … (more)
This missense variant replaces arginine with histidine at codon 158 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein exhibits a significantly decreased transactivation activity (PMID: 10229196, 12826609, 21343334, 25584008, 28472496) and cell growth control activity (PMID: 10229196, 25584008, 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 18685109, 20522432, 21552135, 31081129, 34540492) and in individuals fulfilling the Chompret criteria for Li-Fraumeni syndrome (PMID: 10486318, 10864200, 17308077, 20455025, 21601526, 23175693, 23894400, 24764719, 25584008, 26014290, 27501770, 28472496, 30092803; Lu et al 2021, DOI: 10.1158/1538-7445.AM2021-810). Ages of onset ranged from childhood to adulthood, and several carriers were reported to be unaffected (PMID: 17308077, 21601526, 27501770, 28472496). This variant has been shown to segregate with disease in multiple families (PMID: 17308077, 21464421, 24764719, 34540492; IARC database), including a family with a proband affected with malignant peritoneal mesothelioma and her five first-degree relatives affected with Li-Fraumeni syndrome spectrum tumors (PMID: 21464421). This variant has been identified in 1/251268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different missense substitutions occurring at the same codon (p.Arg158Gly, p.Arg158Leu and p.Arg158Pro) have been observed in individuals affected with Li-Fraumeni syndrome and have been shown to disrupt TP53 function (ClinVar variation ID: 856171, 528248, 246118). This indicates arginine at this position is a functionally and clinically important residue. Based on the available evidence, this variant is classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000692086.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001906425.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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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: SCV001958234.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Sep 01, 2020)
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no assertion criteria provided
Method: provider interpretation
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Rhabdomyosarcoma
Affected status: yes
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434348.1
First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740428.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Comment:
Comment:
This variant has been previously reported as a heterozygous change in patients with TP53-related cancers and Li-Fraumeni syndrome (PMID: 10486318, 23894400, 20455025, 24764719, 26014290, 23175693, 20522432, 17606709, 21601526, 18685109). Experimental studies have shown that this variant affects TP53 function (PMID: 10229196, 12826609, 25584008, 21343334). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (1/251268) and thus is presumed to be rare. The c.473G>A (p.Arg158His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.473G>A (p.Arg158His) variant is classified as Pathogenic.
Comment:
The frequency of this variant in the general population, 0.000099 (1/10070 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Li Fraumeni Syndrome (LFS), breast cancer, acute myeloid leukemia, and Li Fraumeni Syndrome associated cancers (PMIDs: 33372952 (2020), 32427313 (2020), 31105275 (2019), 31081129 (2019), 27501770 (2016), 26014290 (2015), 23894400 (2013), 22186996 (2012), 21761402 (2012), 21601526 (2011), 21464421 (2011)). Published functional studies have reported that this variant results in a damaging affect on TP53 protein function (PMIDs: 28472496 (2017), 25584008 (2015), 20522432 (2010), IARC TP53 https://p53.iarc.fr/). Based on the available information, this variant is classified as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). This variant is present in population databases (rs587782144, gnomAD 0.01%). This missense change has been observed in individuals with TP53-related cancers (PMID: 10486318, 17606709, 18685109, 20455025, 20522432, 21601526, 23175693, 23894400, 24764719, 26014290). It has also been observed to segregate with disease in related individuals. This variant is also known as c.12407G>A. ClinVar contains an entry for this variant (Variation ID: 141963). 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: 10229196, 12826609, 21343334, 25584008). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21464421, 17308077]. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 10229196].
Comment:
The p.R158H pathogenic mutation (also known as c.473G>A) is located in coding exon 4 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 473. The arginine at codon 158 is replaced by histidine, an amino acid with some highly similar properties. This alteration has been reported in multiple individuals with clinical histories suspicious for Li-Fraumeni syndrome, with ages of onset ranging from childhood to adulthood (Varley JM et al. Am J Hum Genet. 1999; 65:995-1006; Villani A et al. Lancet Oncol. 2011 Jun;12(6):559-67; Mitchell G et al. PLoS One. 2013 Jul 22;8(7):e69026; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8; Bougeard GJ et al. J Med Genet. 2008 Aug;45(8):535-8; Wasserman JD et al. J. Clin. Oncol. 2015 Feb;33:602-9; Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812; Stjepanovic N et al. BMC Med Genomics. 2018 Aug;11(1):65). In a study of 214 French families with Li-Fraumeni syndrome, this alteration was identified in eight families; six of these families had cases of adrenocortical carcinoma (Bougeard G et al. J. Clin. Oncol., 2015 Jul;33:2345-52). This alteration is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based studies (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). 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). In addition, a recent functional study demonstrated that the reduction in transcriptional activity and DNA binding resulting from this amino acid substitution is similar to that observed in null mutations (Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812). Furthermore, three different TP53 missense mutations at the same codon have been reported to be associated with Li-Fraumeni syndrome: p.R158G, p.R158P, and p.R158C (Chompret A et al. Br J Cancer. 2000; 82(12):1932-7; Morgan JE et al. Hum Mutat. 2010;31(4):484-91; Herrmann LJ et al. J Clin Endocrinol Metab. 2012 Mar;97(3):E476-85). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Published functional studies demonstrate partial to non-functional transactivation, intermediate levels of growth suppression and colony reduction (PMID: 29979965, 11429705, 12826609, 21343334, 25584008, 10229196); Observed in a few individuals not meeting classic Li-Fraumeni syndrome criteria but several with adrenocortical carcinoma (ACC), leading some authors to suggest this variant might cause reduced penetrance or later onset of tumors other than ACC similar to the TP53 Arg337His Brazilian founder variant (PMID: 26014290, 20455025, 21464421); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20308654, 14559903, 9738975, 21665242, 24590827, 22768918, 27343442, 24764719, 12826609, 26786923, 16494995, 17311302, 21761402, 23894400, 27619989, 18511570, 25584008, 11896595, 9115587, 9399658, 10519380, 12917626, 20522432, 20455025, 21343334, 21464421, 20593220, 21552135, 21601526, 23117049, 25773284, 24829203, 24868540, 24198462, 19671995, 26014290, 23175693, 10486318, 10229196, 28369373, 27501770, 27157322, 28408749, 18685109, 29085664, 28749946, 28466600, 28922847, 28597078, 29058986, 27844328, 25234657, 22170717, 21339461, 10864200, 28349240, 27328919, 25741868, 29755662, 29707145, 28887601, 28724667, 17606709, 11429705, 17308077, 29300620, 29979965, 31016814, 30840781, 31081129, 30092803, 30224644, 31494577, 31447099, 30720243, 31105275, 32427313, 32817165, 33372952, 34240179, 31721094, 33858029, 34308104, 34863587, 35974385, 35418818, 34273903, 35988656, 36495689, 37461096, 12909720, 28472496, 15510160, 37179382)
Comment:
The c.473G>A (p.Arg158His) variant in the TP53 gene has been reported in mulitple patients/families with cancers (PMID 10486318, 17308077, 20522432, 21552135, 21761402, 23175693, 23894400 and 24764719). This variant is observed with a low minor allele frequency in the gnomAD database (1/246110). This variant is at a mutation hotspot of the DNA binding domain where other pathogenic variants in the nearby region have been reported. Functional studies demonstrated decrease P53 functionality (PMID 17606709, 21343334 and 28472496). Therefore, the c.473G>A (p.Arg158His) variant in the TP53 gene is classified as pathogenic.
Comment:
Variant summary: TP53 c.473G>A (p.Arg158His) 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 4e-06 in 251268 control chromosomes.c.473G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (LFS) or LFS spectrum tumors (e.g. Varley_1999, Bougeard_2008, Ceelen_2011); and at least one of these reports described co-segregation of the variant with Li-Fraumeni Syndrome in one family (Ceelen_2011). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function and demonstrated reduced overall transcription activity (TA) on several different promoters (e.g. Monti_2011, Wasserman_2015). Ten 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/likely pathogenic. Several different missense changes involving this codon (p.Arg158Leu, p.Arg158Gly, p.Arg158Cys, Arg158Pro) have been reported in individuals with TP53-related conditions (HGMD), indicating that this amino acid is important for TP53 function. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). This variant is not observed at significant frequency in large population cohorts (gnomAD) . This missense change has been observed in individuals with TP53-related cancers (PMID: 10486318, 17606709, 18685109, 20455025, 20522432, 21601526, 23175693, 23894400, 24764719, 26014290). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 141963). In silico analysis supports that this missense variant has a deleterious effect on protein structure/function. Also,advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, aminoacid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TP53 protein function. (PMID: 10229196, 12826609, 21343334, 25584008). For these reasons, this variant has been classified as Pathogenic.
Comment:
This missense variant replaces arginine with histidine at codon 158 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein exhibits a significantly decreased transactivation activity (PMID: 10229196, 12826609, 21343334, 25584008, 28472496) and cell growth control activity (PMID: 10229196, 25584008, 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 18685109, 20522432, 21552135, 31081129, 34540492) and in individuals fulfilling the Chompret criteria for Li-Fraumeni syndrome (PMID: 10486318, 10864200, 17308077, 20455025, 21601526, 23175693, 23894400, 24764719, 25584008, 26014290, 27501770, 28472496, 30092803; Lu et al 2021, DOI: 10.1158/1538-7445.AM2021-810). Ages of onset ranged from childhood to adulthood, and several carriers were reported to be unaffected (PMID: 17308077, 21601526, 27501770, 28472496). This variant has been shown to segregate with disease in multiple families (PMID: 17308077, 21464421, 24764719, 34540492; IARC database), including a family with a proband affected with malignant peritoneal mesothelioma and her five first-degree relatives affected with Li-Fraumeni syndrome spectrum tumors (PMID: 21464421). This variant has been identified in 1/251268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different missense substitutions occurring at the same codon (p.Arg158Gly, p.Arg158Leu and p.Arg158Pro) have been observed in individuals affected with Li-Fraumeni syndrome and have been shown to disrupt TP53 function (ClinVar variation ID: 856171, 528248, 246118). This indicates arginine at this position is a functionally and clinically important residue. Based on the available evidence, this variant is classified as Pathogenic.
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:
proposed classification - variant undergoing re-assessment, contact laboratory
Comment:
This variant has been previously reported as a heterozygous change in patients with TP53-related cancers and Li-Fraumeni syndrome (PMID: 10486318, 23894400, 20455025, 24764719, 26014290, 23175693, 20522432, 17606709, 21601526, 18685109). Experimental studies have shown that this variant affects TP53 function (PMID: 10229196, 12826609, 25584008, 21343334). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0003% (1/251268) and thus is presumed to be rare. The c.473G>A (p.Arg158His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.473G>A (p.Arg158His) variant is classified as Pathogenic.
Comment:
The frequency of this variant in the general population, 0.000099 (1/10070 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with Li Fraumeni Syndrome (LFS), breast cancer, acute myeloid leukemia, and Li Fraumeni Syndrome associated cancers (PMIDs: 33372952 (2020), 32427313 (2020), 31105275 (2019), 31081129 (2019), 27501770 (2016), 26014290 (2015), 23894400 (2013), 22186996 (2012), 21761402 (2012), 21601526 (2011), 21464421 (2011)). Published functional studies have reported that this variant results in a damaging affect on TP53 protein function (PMIDs: 28472496 (2017), 25584008 (2015), 20522432 (2010), IARC TP53 https://p53.iarc.fr/). Based on the available information, this variant is classified as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). This variant is present in population databases (rs587782144, gnomAD 0.01%). This missense change has been observed in individuals with TP53-related cancers (PMID: 10486318, 17606709, 18685109, 20455025, 20522432, 21601526, 23175693, 23894400, 24764719, 26014290). It has also been observed to segregate with disease in related individuals. This variant is also known as c.12407G>A. ClinVar contains an entry for this variant (Variation ID: 141963). 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: 10229196, 12826609, 21343334, 25584008). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21464421, 17308077]. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 10229196].
Comment:
The p.R158H pathogenic mutation (also known as c.473G>A) is located in coding exon 4 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 473. The arginine at codon 158 is replaced by histidine, an amino acid with some highly similar properties. This alteration has been reported in multiple individuals with clinical histories suspicious for Li-Fraumeni syndrome, with ages of onset ranging from childhood to adulthood (Varley JM et al. Am J Hum Genet. 1999; 65:995-1006; Villani A et al. Lancet Oncol. 2011 Jun;12(6):559-67; Mitchell G et al. PLoS One. 2013 Jul 22;8(7):e69026; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8; Bougeard GJ et al. J Med Genet. 2008 Aug;45(8):535-8; Wasserman JD et al. J. Clin. Oncol. 2015 Feb;33:602-9; Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812; Stjepanovic N et al. BMC Med Genomics. 2018 Aug;11(1):65). In a study of 214 French families with Li-Fraumeni syndrome, this alteration was identified in eight families; six of these families had cases of adrenocortical carcinoma (Bougeard G et al. J. Clin. Oncol., 2015 Jul;33:2345-52). This alteration is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based studies (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). 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). In addition, a recent functional study demonstrated that the reduction in transcriptional activity and DNA binding resulting from this amino acid substitution is similar to that observed in null mutations (Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812). Furthermore, three different TP53 missense mutations at the same codon have been reported to be associated with Li-Fraumeni syndrome: p.R158G, p.R158P, and p.R158C (Chompret A et al. Br J Cancer. 2000; 82(12):1932-7; Morgan JE et al. Hum Mutat. 2010;31(4):484-91; Herrmann LJ et al. J Clin Endocrinol Metab. 2012 Mar;97(3):E476-85). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
Published functional studies demonstrate partial to non-functional transactivation, intermediate levels of growth suppression and colony reduction (PMID: 29979965, 11429705, 12826609, 21343334, 25584008, 10229196); Observed in a few individuals not meeting classic Li-Fraumeni syndrome criteria but several with adrenocortical carcinoma (ACC), leading some authors to suggest this variant might cause reduced penetrance or later onset of tumors other than ACC similar to the TP53 Arg337His Brazilian founder variant (PMID: 26014290, 20455025, 21464421); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20308654, 14559903, 9738975, 21665242, 24590827, 22768918, 27343442, 24764719, 12826609, 26786923, 16494995, 17311302, 21761402, 23894400, 27619989, 18511570, 25584008, 11896595, 9115587, 9399658, 10519380, 12917626, 20522432, 20455025, 21343334, 21464421, 20593220, 21552135, 21601526, 23117049, 25773284, 24829203, 24868540, 24198462, 19671995, 26014290, 23175693, 10486318, 10229196, 28369373, 27501770, 27157322, 28408749, 18685109, 29085664, 28749946, 28466600, 28922847, 28597078, 29058986, 27844328, 25234657, 22170717, 21339461, 10864200, 28349240, 27328919, 25741868, 29755662, 29707145, 28887601, 28724667, 17606709, 11429705, 17308077, 29300620, 29979965, 31016814, 30840781, 31081129, 30092803, 30224644, 31494577, 31447099, 30720243, 31105275, 32427313, 32817165, 33372952, 34240179, 31721094, 33858029, 34308104, 34863587, 35974385, 35418818, 34273903, 35988656, 36495689, 37461096, 12909720, 28472496, 15510160, 37179382)
Comment:
The c.473G>A (p.Arg158His) variant in the TP53 gene has been reported in mulitple patients/families with cancers (PMID 10486318, 17308077, 20522432, 21552135, 21761402, 23175693, 23894400 and 24764719). This variant is observed with a low minor allele frequency in the gnomAD database (1/246110). This variant is at a mutation hotspot of the DNA binding domain where other pathogenic variants in the nearby region have been reported. Functional studies demonstrated decrease P53 functionality (PMID 17606709, 21343334 and 28472496). Therefore, the c.473G>A (p.Arg158His) variant in the TP53 gene is classified as pathogenic.
Comment:
Variant summary: TP53 c.473G>A (p.Arg158His) 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 4e-06 in 251268 control chromosomes.c.473G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (LFS) or LFS spectrum tumors (e.g. Varley_1999, Bougeard_2008, Ceelen_2011); and at least one of these reports described co-segregation of the variant with Li-Fraumeni Syndrome in one family (Ceelen_2011). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function and demonstrated reduced overall transcription activity (TA) on several different promoters (e.g. Monti_2011, Wasserman_2015). Ten 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/likely pathogenic. Several different missense changes involving this codon (p.Arg158Leu, p.Arg158Gly, p.Arg158Cys, Arg158Pro) have been reported in individuals with TP53-related conditions (HGMD), indicating that this amino acid is important for TP53 function. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 158 of the TP53 protein (p.Arg158His). This variant is not observed at significant frequency in large population cohorts (gnomAD) . This missense change has been observed in individuals with TP53-related cancers (PMID: 10486318, 17606709, 18685109, 20455025, 20522432, 21601526, 23175693, 23894400, 24764719, 26014290). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 141963). In silico analysis supports that this missense variant has a deleterious effect on protein structure/function. Also,advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, aminoacid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TP53 protein function. (PMID: 10229196, 12826609, 21343334, 25584008). For these reasons, this variant has been classified as Pathogenic.
Comment:
This missense variant replaces arginine with histidine at codon 158 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein exhibits a significantly decreased transactivation activity (PMID: 10229196, 12826609, 21343334, 25584008, 28472496) and cell growth control activity (PMID: 10229196, 25584008, 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 18685109, 20522432, 21552135, 31081129, 34540492) and in individuals fulfilling the Chompret criteria for Li-Fraumeni syndrome (PMID: 10486318, 10864200, 17308077, 20455025, 21601526, 23175693, 23894400, 24764719, 25584008, 26014290, 27501770, 28472496, 30092803; Lu et al 2021, DOI: 10.1158/1538-7445.AM2021-810). Ages of onset ranged from childhood to adulthood, and several carriers were reported to be unaffected (PMID: 17308077, 21601526, 27501770, 28472496). This variant has been shown to segregate with disease in multiple families (PMID: 17308077, 21464421, 24764719, 34540492; IARC database), including a family with a proband affected with malignant peritoneal mesothelioma and her five first-degree relatives affected with Li-Fraumeni syndrome spectrum tumors (PMID: 21464421). This variant has been identified in 1/251268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Multiple different missense substitutions occurring at the same codon (p.Arg158Gly, p.Arg158Leu and p.Arg158Pro) have been observed in individuals affected with Li-Fraumeni syndrome and have been shown to disrupt TP53 function (ClinVar variation ID: 856171, 528248, 246118). This indicates arginine at this position is a functionally and clinically important residue. Based on the available evidence, this variant is classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Multi-Generational Review of Oncologic Tumors in a Family With TP53 Mutation Presenting With a Pediatric Patient With Osteosarcoma and Lung Acinar Adenocarcinoma. | Butt H | Cureus | 2021 | PMID: 34540492 |
| Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group. | Li H | Journal of the National Cancer Institute | 2021 | PMID: 33372952 |
| Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women. | Palmer JR | Journal of the National Cancer Institute | 2020 | PMID: 32427313 |
| Genotype-phenotype associations among panel-based TP53+ subjects. | Rana HQ | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 31105275 |
| Functional characterization of novel germline TP53 variants in Swedish families. | Kharaziha P | Clinical genetics | 2019 | PMID: 31081129 |
| The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
| Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
| Additional germline findings from a tumor profiling program. | Stjepanovic N | BMC medical genomics | 2018 | PMID: 30092803 |
| A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
| Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage. | Zerdoumi Y | Human molecular genetics | 2017 | PMID: 28472496 |
| The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. | Stenson PD | Human genetics | 2017 | PMID: 28349240 |
| Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. | Döhner H | Blood | 2017 | PMID: 27895058 |
| The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. | Stengel A | Leukemia | 2017 | PMID: 27680515 |
| TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. | Welch JS | The New England journal of medicine | 2016 | PMID: 27959731 |
| 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 |
| TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. | Kadia TM | Cancer | 2016 | PMID: 27463065 |
| TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data. | Bouaoun L | Human mutation | 2016 | PMID: 27328919 |
| Genomic Classification and Prognosis in Acute Myeloid Leukemia. | Papaemmanuil E | The New England journal of medicine | 2016 | PMID: 27276561 |
| Genetic testing in a cohort of young patients with HER2-amplified breast cancer. | Eccles DM | Annals of oncology : official journal of the European Society for Medical Oncology | 2016 | PMID: 26681682 |
| Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival. | Mullany LK | Neoplasia (New York, N.Y.) | 2015 | PMID: 26585234 |
| TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. | Hou HA | Blood cancer journal | 2015 | PMID: 26230955 |
| Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. | Bougeard G | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 26014290 |
| TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. | Ok CY | Journal of hematology & oncology | 2015 | PMID: 25952993 |
| Assessing the TP53 marker type in patients treated with or without neoadjuvant chemotherapy for resectable colorectal liver metastases: a p53 Research Group study. | Pilat N | European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology | 2015 | PMID: 25773284 |
| Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. | Richards S | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25741868 |
| Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study. | Wasserman JD | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25584008 |
| Clinical exome sequencing for genetic identification of rare Mendelian disorders. | Lee H | JAMA | 2014 | PMID: 25326637 |
| Lack of toxicity in a patient with germline TP53 mutation treated with radiotherapy. | Wong P | Current oncology (Toronto, Ont.) | 2014 | PMID: 24764719 |
| Mutant p53 in cancer: new functions and therapeutic opportunities. | Muller PA | Cancer cell | 2014 | PMID: 24651012 |
| TP53 and p53 statuses and their clinical impact in diffuse low grade gliomas. | Gillet E | Journal of neuro-oncology | 2014 | PMID: 24590827 |
| High frequency of germline TP53 mutations in a prospective adult-onset sarcoma cohort. | Mitchell G | PloS one | 2013 | PMID: 23894400 |
| Tumor suppressors status in cancer cell line Encyclopedia. | Sonkin D | Molecular oncology | 2013 | PMID: 23639312 |
| Functional characterisation of p53 mutants identified in breast cancers with suboptimal responses to anthracyclines or mitomycin. | Berge EO | Biochimica et biophysica acta | 2013 | PMID: 23246812 |
| Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma. | Raymond VM | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 23175693 |
| A novel hierarchical prognostic model of AML solely based on molecular mutations. | Grossmann V | Blood | 2012 | PMID: 22915647 |
| TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. | Rücker FG | Blood | 2012 | PMID: 22186996 |
| Early onset HER2-positive breast cancer is associated with germline TP53 mutations. | Melhem-Bertrandt A | Cancer | 2012 | PMID: 21761402 |
| Distinctive patterns of p53 protein expression and microsatellite instability in human colorectal cancer. | Nyiraneza C | Human pathology | 2011 | PMID: 21665242 |
| Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. | Villani A | The Lancet. Oncology | 2011 | PMID: 21601526 |
| 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 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. | Jädersten M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21519010 |
| Malignant peritoneal mesothelioma in a patient with Li-Fraumeni syndrome. | Ceelen WP | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21464421 |
| Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
| 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 |
| Survey of familial glioma and role of germline p16INK4A/p14ARF and p53 mutation. | Robertson LB | Familial cancer | 2010 | PMID: 20455025 |
| Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
| Genetic diagnosis of familial breast cancer using clonal sequencing. | Morgan JE | Human mutation | 2010 | PMID: 20127978 |
| Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome. | Shlien A | Proceedings of the National Academy of Sciences of the United States of America | 2008 | PMID: 18685109 |
| Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. | Bougeard G | Journal of medical genetics | 2008 | PMID: 18511570 |
| Transcriptional functionality of germ line p53 mutants influences cancer phenotype. | Monti P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17606709 |
| Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. | Petitjean A | Human mutation | 2007 | PMID: 17311302 |
| Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. | Tabori U | Cancer research | 2007 | PMID: 17308077 |
| Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
| Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. | Kato S | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12826609 |
| A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. | Friedler A | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11782540 |
| P53 germline mutations in childhood cancers and cancer risk for carrier individuals. | Chompret A | British journal of cancer | 2000 | PMID: 10864200 |
| Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors. | Varley JM | American journal of human genetics | 1999 | PMID: 10486318 |
| Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions. | Smith PD | Oncogene | 1999 | PMID: 10229196 |
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Text-mined citations for rs587782144 ...
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Record last updated Nov 03, 2024
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