ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.398T>C (p.Met133Thr)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.398T>C (p.Met133Thr)
Variation ID: 12357 Accession: VCV000012357.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7675214 (GRCh38) [ NCBI UCSC ] 17: 7578532 (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 1, 2017 Feb 14, 2024 Jun 18, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.398T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Met133Thr missense NM_001126112.3:c.398T>C NP_001119584.1:p.Met133Thr missense NM_001126113.3:c.398T>C NP_001119585.1:p.Met133Thr missense NM_001126114.3:c.398T>C NP_001119586.1:p.Met133Thr missense NM_001126115.2:c.2T>C NP_001119587.1:p.Met1Thr missense initiator codon variant NM_001126116.2:c.2T>C NP_001119588.1:p.Met1Thr missense initiator codon variant NM_001126117.2:c.2T>C NP_001119589.1:p.Met1Thr missense initiator codon variant NM_001126118.2:c.281T>C NP_001119590.1:p.Met94Thr missense NM_001276695.3:c.281T>C NP_001263624.1:p.Met94Thr missense NM_001276696.3:c.281T>C NP_001263625.1:p.Met94Thr missense NM_001276697.3:c.-80T>C 5 prime UTR NM_001276698.3:c.-80T>C 5 prime UTR NM_001276699.3:c.-80T>C 5 prime UTR NM_001276760.3:c.281T>C NP_001263689.1:p.Met94Thr missense NM_001276761.3:c.281T>C NP_001263690.1:p.Met94Thr missense NC_000017.11:g.7675214A>G NC_000017.10:g.7578532A>G NG_017013.2:g.17337T>C LRG_321:g.17337T>C P04637:p.Met133Thr - Protein change
- M133T, M1T, M94T
- Other names
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- Canonical SPDI
- NC_000017.11:7675213:A:G
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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
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The frequency of the allele represented by this VCV record.
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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
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. |
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TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3196 | 3291 |
Conditions - Germline
Condition
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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
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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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Pathogenic (2) |
criteria provided, single submitter
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Jun 18, 2022 | RCV000013151.31 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2022 | RCV000492130.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 9, 2021 | RCV001383051.8 |
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
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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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Pathogenic
(Jun 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002582605.2
First in ClinVar: Oct 15, 2022 Last updated: Sep 03, 2023 |
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Pathogenic
(Jun 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002583167.2
First in ClinVar: Oct 15, 2022 Last updated: Sep 03, 2023 |
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Pathogenic
(Dec 13, 2019)
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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: SCV000581145.6
First in ClinVar: Jul 01, 2017 Last updated: Sep 03, 2023 |
Comment:
The p.M133T pathogenic mutation (also known as c.398T>C), located in coding exon 4 of the TP53 gene, results from a T to C substitution at … (more)
The p.M133T pathogenic mutation (also known as c.398T>C), located in coding exon 4 of the TP53 gene, results from a T to C substitution at nucleotide position 398. The methionine at codon 133 is replaced by threonine, an amino acid with some similar properties. This alteration was reported in a large family with Li-Fraumeni syndrome (LFS) and was found to segregate with LFS spectrum tumors in nine affected family members (Law J et al. Cancer Res. 1991 Dec;51:6385-7). In addition, this alteration was detected in a second large pedigree with several LFS tumors, and was found to segregate with disease in three affected family members (Shay J et al. Mol. Cell. Biol. 1995 Jan;15:425-32). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient 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). The p.M133T alteration was also shown to have less than 25% binding capacity to multiple response elements when compared to wild type TP53 (Malcikova J et al. Biol. Chem.;391:197-205). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science 1994 Jul; 265(5170):346-55; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 09, 2021)
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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: SCV001582069.5
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects TP53 protein function (PMID: 20128691, 12826609, 21343334, … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects TP53 protein function (PMID: 20128691, 12826609, 21343334, 29979965, 30224644). This variant has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 1933902, 10477429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12357). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 133 of the TP53 protein (p.Met133Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. (less)
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Pathogenic
(Jan 01, 1999)
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no assertion criteria provided
Method: literature only
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LI-FRAUMENI SYNDROME 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000033398.11
First in ClinVar: Apr 04, 2013 Last updated: Sep 03, 2023 |
Comment on evidence:
In 9 members of an extended family with Li-Fraumeni syndrome-1 (151623), Law et al. (1991) found that a germline mutation at codon 133 (ATG-to-ACG), resulting … (more)
In 9 members of an extended family with Li-Fraumeni syndrome-1 (151623), Law et al. (1991) found that a germline mutation at codon 133 (ATG-to-ACG), resulting in substitution of threonine for methionine (M133T), completely cosegregated with the cancer syndrome. An ATG-to-TTG mutation at codon 133, resulting in substitution of leucine for methionine, had been reported previously in a sporadic cancer of the colon (Nigro et al., 1989). Hung et al. (1999) identified the same M133T mutation in the TP53 gene in 2 large, apparently unrelated African American families, both of which had a high incidence of breast cancer and other tumors characteristic of Li-Fraumeni syndrome. Haplotype analysis revealed that the 2 families shared an identical haplotype. Loss of heterozygosity at the TP53 locus in tumor tissue from each family was observed; in each case, the retained allele carried the common haplotype. The frequency of this haplotype in the general African American population is less than 0.003. This unique haplotype, combined with the rare TP53 mutation, suggested that these African American families share a common ancestry. The second proband of Hung et al. (1999) was from the same family as that in which Law et al. (1991) had originally described the M133T mutation in relation to Li-Fraumeni syndrome. (less)
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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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 |
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
A molecular signature of normal breast epithelial and stromal cells from Li-Fraumeni syndrome mutation carriers. | Herbert BS | Oncotarget | 2010 | PMID: 21311097 |
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 |
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 |
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 |
TP53 mutation and haplotype analysis of two large African American families. | Hung J | Human mutation | 1999 | PMID: 10477429 |
Spontaneous in vitro immortalization of breast epithelial cells from a patient with Li-Fraumeni syndrome. | Shay JW | Molecular and cellular biology | 1995 | PMID: 7799951 |
A germ line mutation in exon 5 of the p53 gene in an extended cancer family. | Law JC | Cancer research | 1991 | PMID: 1933902 |
Mutations in the p53 gene occur in diverse human tumour types. | Nigro JM | Nature | 1989 | PMID: 2531845 |
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Text-mined citations for rs28934873 ...
HelpRecord last updated Feb 20, 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.