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. 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. ClinVar contains an entry for this variant (Variation ID: 2185665). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 173 of the TP53 protein (p.Val173Leu).
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.517G>C (p.Val173Leu)
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.
(2)
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)
Pathogenic(1); Uncertain significance(1)
2
criteria provided, conflicting classifications
Somatic
Clinical impact
Help
The aggregate somatic clinical impact for this variant for one or more tumor types, using the AMP/ASCO/CAP terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(1)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate somatic clinical impact 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.
1
criteria provided, single submitter
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.517G>C (p.Val173Leu)
Variation ID: 2185665 Accession: VCV002185665.4
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.1 17: 7675095 (GRCh38) [ NCBI UCSC ] 17: 7578413 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 8, 2023 May 1, 2024 Feb 16, 2024 Somatic - Clinical impact Sep 1, 2024 Sep 1, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.517G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Val173Leu missense NM_000546.4:c.517G>C NM_001126112.3:c.517G>C NP_001119584.1:p.Val173Leu missense NM_001126113.3:c.517G>C NP_001119585.1:p.Val173Leu missense NM_001126114.3:c.517G>C NP_001119586.1:p.Val173Leu missense NM_001126115.2:c.121G>C NP_001119587.1:p.Val41Leu missense NM_001126116.2:c.121G>C NP_001119588.1:p.Val41Leu missense NM_001126117.2:c.121G>C NP_001119589.1:p.Val41Leu missense NM_001126118.2:c.400G>C NP_001119590.1:p.Val134Leu missense NM_001276695.3:c.400G>C NP_001263624.1:p.Val134Leu missense NM_001276696.3:c.400G>C NP_001263625.1:p.Val134Leu missense NM_001276697.3:c.40G>C NP_001263626.1:p.Val14Leu missense NM_001276698.3:c.40G>C NP_001263627.1:p.Val14Leu missense NM_001276699.3:c.40G>C NP_001263628.1:p.Val14Leu missense NM_001276760.3:c.400G>C NP_001263689.1:p.Val134Leu missense NM_001276761.3:c.400G>C NP_001263690.1:p.Val134Leu missense NM_001407262.1:c.517G>C NP_001394191.1:p.Val173Leu missense NM_001407263.1:c.400G>C NP_001394192.1:p.Val134Leu missense NM_001407264.1:c.517G>C NP_001394193.1:p.Val173Leu missense NM_001407265.1:c.400G>C NP_001394194.1:p.Val134Leu missense NM_001407266.1:c.517G>C NP_001394195.1:p.Val173Leu missense NM_001407267.1:c.400G>C NP_001394196.1:p.Val134Leu missense NM_001407268.1:c.517G>C NP_001394197.1:p.Val173Leu missense NM_001407269.1:c.400G>C NP_001394198.1:p.Val134Leu missense NM_001407270.1:c.517G>C NP_001394199.1:p.Val173Leu missense NM_001407271.1:c.400G>C NP_001394200.1:p.Val134Leu missense NR_176326.1:n.659G>C NC_000017.11:g.7675095C>G NC_000017.10:g.7578413C>G NG_017013.2:g.17456G>C LRG_321:g.17456G>C LRG_321t1:c.517G>C LRG_321p1:p.Val173Leu LRG_321t2:c.517G>C LRG_321:p.Val173Leu LRG_321t3:c.517G>C LRG_321p3:p.Val173Leu LRG_321t4:c.517G>C LRG_321p4:p.Val173Leu LRG_321t5:c.121G>C LRG_321p5:p.Val41Leu LRG_321t6:c.121G>C LRG_321p6:p.Val41Leu LRG_321t7:c.121G>C LRG_321p7:p.Val41Leu LRG_321t8:c.400G>C LRG_321p8:p.Val134Leu - Protein change
- V134L, V173L, V41L, V14L
- Other names
- -
- Canonical SPDI
- NC_000017.11:7675094:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 |
3368 | 3467 | |
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. |
|---|---|---|---|---|
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 25, 2023 | RCV002596262.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 16, 2024 | RCV004069069.1 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jun 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003503685.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
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 … (more)
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. 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. ClinVar contains an entry for this variant (Variation ID: 2185665). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 173 of the TP53 protein (p.Val173Leu). (less)
|
|
|
Pathogenic
(Feb 16, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV005036125.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The p.V173L pathogenic mutation (also known as c.517G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at … (more)
The p.V173L pathogenic mutation (also known as c.517G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 517. The valine at codon 173 is replaced by leucine, an amino acid with highly similar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with Li Fraumeni syndrome (LFS) (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (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 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). Additional alterations at the same codon, p.V173L (c.517G>T) and p.V173M (c.517G>A), have demonstrated abnormal function in functional assays, and p.V173M has been detected in a family meeting clinical criteria for Li-Fraumeni Syndrome (Achatz M et al. Cancer Lett. 2007 Jan; 245(1-2):96-102). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
Comment:
Comment:
The p.V173L pathogenic mutation (also known as c.517G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 517. The valine at codon 173 is replaced by leucine, an amino acid with highly similar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with Li Fraumeni syndrome (LFS) (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (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 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). Additional alterations at the same codon, p.V173L (c.517G>T) and p.V173M (c.517G>A), have demonstrated abnormal function in functional assays, and p.V173M has been detected in a family meeting clinical criteria for Li-Fraumeni Syndrome (Achatz M et al. Cancer Lett. 2007 Jan; 245(1-2):96-102). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is not present in population databases (gnomAD no frequency) and it is reported in Clinvar as conflicting of pathogenicity. This missense change has been observed as a somatic variant in an individual with Dicer1-sarcoma. In silico algorithms suggest that this variant is deleterius.
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:
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. 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. ClinVar contains an entry for this variant (Variation ID: 2185665). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 173 of the TP53 protein (p.Val173Leu).
Comment:
The p.V173L pathogenic mutation (also known as c.517G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 517. The valine at codon 173 is replaced by leucine, an amino acid with highly similar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with Li Fraumeni syndrome (LFS) (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (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 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). Additional alterations at the same codon, p.V173L (c.517G>T) and p.V173M (c.517G>A), have demonstrated abnormal function in functional assays, and p.V173M has been detected in a family meeting clinical criteria for Li-Fraumeni Syndrome (Achatz M et al. Cancer Lett. 2007 Jan; 245(1-2):96-102). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is not present in population databases (gnomAD no frequency) and it is reported in Clinvar as conflicting of pathogenicity. This missense change has been observed as a somatic variant in an individual with Dicer1-sarcoma. In silico algorithms suggest that this variant is deleterius.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| 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 |
Conditions - Somatic
| Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
|---|---|---|---|---|
|
Tier III Unknown
(1)
|
Jul 31, 2024 | RCV004698434.1 |
Submissions - Somatic
|
Clinical impact
Help
The submitted somatic clinical impact 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) |
Tumor type
Help
The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
Tier III Unknown
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Primary intracranial sarcoma, DICER1-mutant
Affected status: unknown
Allele origin:
somatic
|
Molecular Pathology Unit, Bambino Gesu' Children's Hospital, IRCCS
Accession: SCV005200118.1
First In ClinVar: Sep 01, 2024 Last updated: Sep 01, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency) and it is reported in Clinvar as conflicting of pathogenicity. This missense change has … (more)
This variant is not present in population databases (gnomAD no frequency) and it is reported in Clinvar as conflicting of pathogenicity. This missense change has been observed as a somatic variant in an individual with Dicer1-sarcoma. In silico algorithms suggest that this variant is deleterius. (less)
|
Comment:
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. 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. ClinVar contains an entry for this variant (Variation ID: 2185665). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 173 of the TP53 protein (p.Val173Leu).
Comment:
The p.V173L pathogenic mutation (also known as c.517G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 517. The valine at codon 173 is replaced by leucine, an amino acid with highly similar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with Li Fraumeni syndrome (LFS) (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (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 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). Additional alterations at the same codon, p.V173L (c.517G>T) and p.V173M (c.517G>A), have demonstrated abnormal function in functional assays, and p.V173M has been detected in a family meeting clinical criteria for Li-Fraumeni Syndrome (Achatz M et al. Cancer Lett. 2007 Jan; 245(1-2):96-102). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
This variant is not present in population databases (gnomAD no frequency) and it is reported in Clinvar as conflicting of pathogenicity. This missense change has been observed as a somatic variant in an individual with Dicer1-sarcoma. In silico algorithms suggest that this variant is deleterius.
Citations for somatic classification of this variant
Help| There are no citations for somatic classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for this variant ...
HelpRecord last updated Nov 10, 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.