ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.1060C>A (p.Gln354Lys)
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.1060C>A (p.Gln354Lys)
Variation ID: 231485 Accession: VCV000231485.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7670649 (GRCh38) [ NCBI UCSC ] 17: 7573967 (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 May 12, 2018 Apr 20, 2024 Aug 2, 2021 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.1060C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Gln354Lys missense NM_001126112.3:c.1060C>A NP_001119584.1:p.Gln354Lys missense NM_001126113.3:c.*79C>A 3 prime UTR NM_001126114.3:c.*167C>A 3 prime UTR NM_001126115.2:c.664C>A NP_001119587.1:p.Gln222Lys missense NM_001126116.2:c.*167C>A 3 prime UTR NM_001126117.2:c.*79C>A 3 prime UTR NM_001126118.2:c.943C>A NP_001119590.1:p.Gln315Lys missense NM_001276695.3:c.*79C>A 3 prime UTR NM_001276696.3:c.*167C>A 3 prime UTR NM_001276697.3:c.583C>A NP_001263626.1:p.Gln195Lys missense NM_001276698.3:c.*167C>A 3 prime UTR NM_001276699.3:c.*79C>A 3 prime UTR NM_001276760.3:c.943C>A NP_001263689.1:p.Gln315Lys missense NM_001276761.3:c.943C>A NP_001263690.1:p.Gln315Lys missense NC_000017.11:g.7670649G>T NC_000017.10:g.7573967G>T NG_017013.2:g.21902C>A LRG_321:g.21902C>A LRG_321t1:c.1060C>A LRG_321p1:p.Gln354Lys P04637:p.Gln354Lys - Protein change
- Q222K, Q315K, Q354K, Q195K
- Other names
- NM_000546.5(TP53):c.1060C>A
- Canonical SPDI
- NC_000017.11:7670648:G: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.
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 | ||
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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 |
3211 | 3306 |
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
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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. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Feb 16, 2023 | RCV000222255.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 30, 2023 | RCV000469791.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 1, 2017 | RCV000626710.4 | |
Likely benign (3) |
reviewed by expert panel
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Aug 2, 2021 | RCV000663226.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 27, 2020 | RCV001269248.3 |
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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Likely benign
(Aug 02, 2021)
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reviewed by expert panel
Method: curation
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None
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen TP53 Variant Curation Expert Panel, ClinGen
Accession: SCV001949924.1
First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Comment:
Transactivation assays show supertransactivation function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according … (more)
Transactivation assays show supertransactivation function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). This variant has been observed in 4 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributors). In summary, TP53 c.1060C>A (p.Gln354Lys) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BP4, BS2_Supporting. (less)
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Uncertain significance
(Jan 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Colorectal polyposis
Colonic neoplasm
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747413.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
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Uncertain significance
(May 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000786422.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Uncertain significance
(Nov 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001448570.1
First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020 |
Comment:
Variant summary: TP53 c.1060C>A (p.Gln354Lys) results in a conservative amino acid change located in the p53, tetramerization domain (IPR010991) of the encoded protein sequence. Five … (more)
Variant summary: TP53 c.1060C>A (p.Gln354Lys) results in a conservative amino acid change located in the p53, tetramerization domain (IPR010991) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250864 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1060C>A has been reported in the literature in at-least one individual affected with breast cancer (example, Castero_2014). This report(s) does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Kato_2003). These results showed no damaging effect of this variant based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Five 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Likely benign
(Jan 24, 2022)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002530422.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely benign
(Feb 02, 2021)
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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: SCV000275352.6
First in ClinVar: May 29, 2016 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Apr 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004017866.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Uncertain significance
(Feb 16, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV001359324.3
First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glutamine with lysine at codon 354 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glutamine with lysine at codon 354 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant was functional in yeast transactivation assays (PMID: 12826609) and did not demonstrate dominant-negative or loss-of-function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 24549055, 33471991) but also in controls and individuals unselected for cancer (PMID: 28861920, 33471991). This variant has been identified in 5/250864 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Oct 30, 2023)
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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: SCV000545335.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 354 of the TP53 protein (p.Gln354Lys). … (more)
This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 354 of the TP53 protein (p.Gln354Lys). This variant is present in population databases (rs755394212, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24549055, 34326862). ClinVar contains an entry for this variant (Variation ID: 231485). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609). 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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Uncertain Significance
(Sep 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004823723.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This missense variant replaces glutamine with lysine at codon 354 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glutamine with lysine at codon 354 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant was functional in yeast transactivation assays (PMID: 12826609) and did not demonstrate dominant-negative or loss-of-function in human cell growth suppression assays (PMID: 30224644). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 24549055, 33471991) but also in controls and individuals unselected for cancer (PMID: 28861920, 33471991). This variant has been identified in 5/250864 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
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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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Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. | Bhai P | Frontiers in genetics | 2021 | PMID: 34326862 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
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 |
Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history. | de Andrade KC | Human mutation | 2017 | PMID: 28861920 |
Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. | Castéra L | European journal of human genetics : EJHG | 2014 | PMID: 24549055 |
Cancer-associated p53 tetramerization domain mutants: quantitative analysis reveals a low threshold for tumor suppressor inactivation. | Kamada R | The Journal of biological chemistry | 2011 | PMID: 20978130 |
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 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/84fd8478-98b3-4da0-a569-c3ef1e09753e | - | - | - | - |
Text-mined citations for rs755394212 ...
HelpRecord last updated Apr 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.