ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.559G>C (p.Gly187Arg)
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.
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.
Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.559G>C (p.Gly187Arg)
Variation ID: 635392 Accession: VCV000635392.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7675053 (GRCh38) [ NCBI UCSC ] 17: 7578371 (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 Jul 6, 2019 May 1, 2024 Oct 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.559G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Gly187Arg missense NM_001126112.3:c.559G>C NP_001119584.1:p.Gly187Arg missense NM_001126113.3:c.559G>C NP_001119585.1:p.Gly187Arg missense NM_001126114.3:c.559G>C NP_001119586.1:p.Gly187Arg missense NM_001126115.2:c.163G>C NP_001119587.1:p.Gly55Arg missense NM_001126116.2:c.163G>C NP_001119588.1:p.Gly55Arg missense NM_001126117.2:c.163G>C NP_001119589.1:p.Gly55Arg missense NM_001126118.2:c.442G>C NP_001119590.1:p.Gly148Arg missense NM_001276695.3:c.442G>C NP_001263624.1:p.Gly148Arg missense NM_001276696.3:c.442G>C NP_001263625.1:p.Gly148Arg missense NM_001276697.3:c.82G>C NP_001263626.1:p.Gly28Arg missense NM_001276698.3:c.82G>C NP_001263627.1:p.Gly28Arg missense NM_001276699.3:c.82G>C NP_001263628.1:p.Gly28Arg missense NM_001276760.3:c.442G>C NP_001263689.1:p.Gly148Arg missense NM_001276761.3:c.442G>C NP_001263690.1:p.Gly148Arg missense NC_000017.11:g.7675053C>G NC_000017.10:g.7578371C>G NG_017013.2:g.17498G>C LRG_321:g.17498G>C LRG_321t1:c.559G>C LRG_321p1:p.Gly187Arg - Protein change
- G148R, G187R, G55R, G28R
- Other names
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- Canonical SPDI
- NC_000017.11:7675052:C:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- sequence_variant_affecting_splicing Sequence Ontology [SO:1000071]
- Intron inclusion between exons 5 & 6, or skiping end of exon 5, based on review of RNA-seq in HPAC cancer cell line which has TP53 NM_000546.5:c.559G>C variant. [submitted by MutSpliceDB: a database of splice sites variants effects on splicing, NIH]
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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
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The frequency of the allele represented by this VCV record.
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- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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. |
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TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3307 | 3402 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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not provided (1) |
no classification provided
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- | RCV000786835.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 14, 2020 | RCV001302589.7 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 23, 2023 | RCV002343642.3 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 12, 2022 | RCV002292581.2 |
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
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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
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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
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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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Uncertain significance
(Jun 14, 2020)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001491803.4
First in ClinVar: Mar 07, 2021 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine with arginine at codon 187 of the TP53 protein (p.Gly187Arg). The glycine residue is moderately conserved and there is a … (more)
This sequence change replaces glycine with arginine at codon 187 of the TP53 protein (p.Gly187Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant also falls at the last nucleotide of exon 5 of the TP53 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Li Fraumeni syndrome (PMID: 30239254). ClinVar contains an entry for this variant (Variation ID: 635392). This variant has been reported not to substantially affect TP53 protein function (PMID: 12826609, 29979965, 30224644). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely pathogenic
(Oct 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002651396.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.559G>C variant (also known as p.G187R), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide … (more)
The c.559G>C variant (also known as p.G187R), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 559. This change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the glycine at codon 187 to arginine, an amino acid with dissimilar properties. This alteration was reported in multiple generations of a family meeting Chompret criteria (Doyle MR et al. Pediatr Hematol Oncol, 2018 Apr;35:203-207). This variant is in the DNA binding domain of the TP53 protein and is reported to have transactivation similar to wild type in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9), and studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387), however, these assays do not measure the impact of potential splice defects. This nucleotide position is highly conserved in available vertebrate species, and this amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
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Pathogenic
(Jul 12, 2022)
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no assertion criteria provided
Method: clinical testing
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Li-Fraumeni syndrome 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Hereditary Cancer Clinic, Medical College of Georgia
Accession: SCV002584908.1
First in ClinVar: Oct 22, 2022 Last updated: Oct 22, 2022 |
Comment:
PP3: Variant is predicted splicing: scSNV-ADA = 0.999973 is greater than 0.999925, and LOF in gene TP53 is known to cause disease (gene has 620 … (more)
PP3: Variant is predicted splicing: scSNV-ADA = 0.999973 is greater than 0.999925, and LOF in gene TP53 is known to cause disease (gene has 620 reported pathogenic LOF variants), furthermore BayesDel_addAF = 0.296 is between 0.22 and 0.421 ? moderate pathogenic. PM1: Hot-spot of length 17 amino-acids has 52 missense/in-frame variants (10 pathogenic variants, 42 uncertain variants and no benign), which qualifies as supporting pathogenic. PM2: Variant not found in gnomAD genomes, good gnomAD genomes coverage = 32.5. (less)
Clinical Features:
Adrenal cortex carcinoma (present)
Age: 0-9 years
Sex: male
Comment on evidence:
Left adrenocortical carcinoma. Right gluteal embryonal rhabdomyosarcoma (somatic TP53 VAF 93%). Father colorectal cancer germline positive. Paternal grandmother breast cancer twice, pancreas cancer, germline positive. … (more)
Left adrenocortical carcinoma. Right gluteal embryonal rhabdomyosarcoma (somatic TP53 VAF 93%). Father colorectal cancer germline positive. Paternal grandmother breast cancer twice, pancreas cancer, germline positive. Brother unaffected and germline negative. (less)
Testing laboratory: ARUP
Date variant was reported to submitter: 2016-04-08
Testing laboratory interpretation: Uncertain significance
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not provided
(-)
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no classification provided
Method: in vitro
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not provided
Affected status: not applicable
Allele origin:
not applicable
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MutSpliceDB: a database of splice sites variants effects on splicing, NIH
Accession: SCV000925729.2
First in ClinVar: Jul 06, 2019 Last updated: Jul 06, 2019 |
Method: Based on review of RNA-seq data in sample with variant.
Result:
Intron inclusion between exons 5 & 6, or skiping end of exon 5
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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sequence_variant_affecting_splicing
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MutSpliceDB: a database of splice sites variants effects on splicing, NIH
Accession: SCV000925729.2
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Comment:
Intron inclusion between exons 5 & 6, or skiping end of exon 5, based on review of RNA-seq in HPAC cancer cell line which has … (more)
Intron inclusion between exons 5 & 6, or skiping end of exon 5, based on review of RNA-seq in HPAC cancer cell line which has TP53 NM_000546.5:c.559G>C variant. (less)
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A quantitative model to predict pathogenicity of missense variants in the TP53 gene. | Fortuno C | Human mutation | 2019 | PMID: 30840781 |
A novel p.Gly187Arg TP53 variant appears to result in Li-Fraumeni syndrome. | Doyle MR | Pediatric hematology and oncology | 2018 | PMID: 30239254 |
Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
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 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
https://brb.nci.nih.gov/cgi-bin/splicing/splicing_evidence.cgi?caid=CA397841073 | - | - | - | - |
Text-mined citations for rs776167460 ...
HelpRecord last updated May 01, 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.