ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.800G>A (p.Arg267Gln)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.800G>A (p.Arg267Gln)
Variation ID: 127823 Accession: VCV000127823.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7673820 (GRCh38) [ NCBI UCSC ] 17: 7577138 (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 Jun 1, 2016 Jun 17, 2024 Aug 11, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.800G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg267Gln missense NM_001126112.3:c.800G>A NP_001119584.1:p.Arg267Gln missense NM_001126113.3:c.800G>A NP_001119585.1:p.Arg267Gln missense NM_001126114.3:c.800G>A NP_001119586.1:p.Arg267Gln missense NM_001126115.2:c.404G>A NP_001119587.1:p.Arg135Gln missense NM_001126116.2:c.404G>A NP_001119588.1:p.Arg135Gln missense NM_001126117.2:c.404G>A NP_001119589.1:p.Arg135Gln missense NM_001126118.2:c.683G>A NP_001119590.1:p.Arg228Gln missense NM_001276695.3:c.683G>A NP_001263624.1:p.Arg228Gln missense NM_001276696.3:c.683G>A NP_001263625.1:p.Arg228Gln missense NM_001276697.3:c.323G>A NP_001263626.1:p.Arg108Gln missense NM_001276698.3:c.323G>A NP_001263627.1:p.Arg108Gln missense NM_001276699.3:c.323G>A NP_001263628.1:p.Arg108Gln missense NM_001276760.3:c.683G>A NP_001263689.1:p.Arg228Gln missense NM_001276761.3:c.683G>A NP_001263690.1:p.Arg228Gln missense NC_000017.11:g.7673820C>T NC_000017.10:g.7577138C>T NG_017013.2:g.18731G>A LRG_321:g.18731G>A LRG_321t1:c.800G>A LRG_321p1:p.Arg267Gln P04637:p.Arg267Gln - Protein change
- R135Q, R228Q, R267Q, R108Q
- Other names
- p.R267Q:CGG>CAG
- Canonical SPDI
- NC_000017.11:7673819: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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 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
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. |
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TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3361 | 3460 |
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. |
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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2024 | RCV000115737.22 | |
Uncertain significance (3) |
reviewed by expert panel
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Aug 11, 2020 | RCV000205433.16 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 18, 2016 | RCV000213058.3 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Apr 11, 2023 | RCV000662441.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 22, 2021 | RCV001358724.3 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001358329.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Mar 19, 2024 | RCV004567016.1 |
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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Uncertain significance
(Aug 11, 2020)
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reviewed by expert panel
Method: curation
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Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen TP53 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV001429619.1 First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Comment:
This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). This variant has been reported in 2 … (more)
This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). This variant has been reported in 2 probands meeting Chrompret criteria (PS4_Supporting; PMID:25584008, internal laboratory contributor). Transactivation assays show partially functional variant 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_Supporting; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.800G>A (p.Arg267Gln) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Expert Panel: PP3, PS4_Supporting, BS3_Supporting. (less)
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Uncertain significance
(Feb 02, 2017)
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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: SCV000784905.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Uncertain significance
(Feb 18, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149646.14
First in ClinVar: May 17, 2014 Last updated: Jun 01, 2016 |
Comment:
This variant is denoted TP53 c.800G>A at the cDNA level, p.Arg267Gln (R267Q) at the protein level, and results in the change of an Arginine to … (more)
This variant is denoted TP53 c.800G>A at the cDNA level, p.Arg267Gln (R267Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has been reported in an affected child from a Li-Fraumeni syndrome family, co-occurring with two other TP53 variants (Quesnel 1999). This variant has also been identified in a woman who had breast cancer at age 49 and a family history of breast, ovarian, and colon cancers; however, the variant was also identified in a 74-year-old unaffected relative (Prosser 1992). TP53 Arg267Gln was reported in a child with adrenocortical carcinoma; however the child's mother also carried the variant and was unaffected, and there was no reported family history of cancer (Wasserman 2015). In addition, this variant has been identified in at least two colon cancer cases (Kandioler 2015). This variant has demonstrated mixed results in studies assessing transactivation activity, and although it has been shown to be deficient in colony reduction and have significantly reduced growth suppressive ability, it has yielded TP53 expression levels comparable to wild type (Quesnel 1999, Jordan 2010, Monti 2011, Wasserman 2015).Population frequency data is not available for TP53 Arg267Gln in the NHLBI Exome Sequencing Project or 1000 Genomes. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Arg267Gln occurs at a position that is not conserved and is located within the region of interaction with E4F1 (UniProt). One published splicing model predicts that TP53 Arg267Gln introduces a new splice acceptor site (Kouidou 2009), however internal splicing models are inconsistent regarding the effect of this variant on splicing. Protein-based in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether TP53 Arg267Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. (less)
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Uncertain significance
(Mar 22, 2021)
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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: SCV001554563.1
First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
Variant summary: TP53 c.800G>A (p.Arg267Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four … (more)
Variant summary: TP53 c.800G>A (p.Arg267Gln) results in a conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249356 control chromosomes. c.800G>A has been reported in the literature in individuals suspected to be affected with Li-Fraumeni Syndrome (e.g. Rines_1998, Quesnel_1999, DiNardo_2016, Swaminathan_2019). However, these reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome, as the variant was detected along with at least one additional TP53 variant of uncertain significance. To our knowledge, no co-segregation studies for the p.Arg267Gln variant in isolation in Li-Fraumeni families have been reported. The variant has also been detected in individuals with other cancer phenotypes, including individuals with breast cancer and adrenocortical carcinoma in which the variant was also found in unaffected family members, suggesting a lack of segregation with disease (e.g. Prosser_1992, Wasserman_2015). The IARC database reports the variant as being partially-functional based on overall transcription activity (TA) on eight different promoters as measured in yeast assays by Kato et al, 2003. These findings have been corroborated by other assays assessing transcriptional activity in yeast, showing a partial reduction in residual transcriptional activity in cells with the variant (e.g. Quesnel_1999, Jordan_2010, Monti_2011). However, an assay using a luciferase-reporter for TP53 activity in human cells lines found activity levels that exceeded wild-type and only mild affects on colony growth compared to wild-type (e.g. Wasserman_2015). Seven other ClinVar submitters (evaluation after 2014), including one expert panel, have all cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Jan 04, 2024)
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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: SCV000686776.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with glutamine at codon 267 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glutamine at codon 267 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 this variant to have a partial defect in transcriptional transactivation activity (PMID: 12826609, 17606709, 20407015, 21343334, 25584008), partial to normal function in human cell growth suppression assays (PMID: 10435620, 25584008, 30224644) and normal function in human cell proliferation assays (PMID: 29979965). This variant has been reported in individuals with suspected Li-Fraumeni syndrome (PMID: 9667734, 10435620, 30709875, 27210295), breast cancer (PMID: 1394133, 1562462, 26225655, 28135048, 29875428, 31060593), colorectal cancer (PMID: 27978560), ovarian cancer (PMID: 16229746), lung cancer (PMID: 28843361), adrenocortical carcinoma (PMID: 25584008), and lymphoma (PMID: 32504211) in the literature. However it has also been found in controls and unaffected family members (PMID: 1562462, 33471991). This variant has been identified in 3/249356 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
(Mar 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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Adrenocortical carcinoma, hereditary
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV005054323.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Uncertain significance
(Mar 17, 2020)
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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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Division of Medical Genetics, University of Washington
Study: CSER_CHARM
Accession: SCV001434316.1 First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020 |
Comment:
This variant has been reported in a child who developed multiple primary cancers during childhood; however, this variant was inherited on the same haplotype as … (more)
This variant has been reported in a child who developed multiple primary cancers during childhood; however, this variant was inherited on the same haplotype as another variant, p.Arg156His (Quesnel 1999). This variant was also observed in a woman with breast cancer at age 49 who had a family history of breast, ovarian, and lung cancers occurring in relatives at mostly older ages (Prosser 2012). An experimental study found that the this variant retained transactivation capacity similar to wild type when exposed to high levels of galactose (Jordan 2015). This variant has an allele frequency of 0.00001203 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico tools evaluating evolutionary conservation and impact on protein structure and function suggest that this variant may have a deleterious effect. Therefore, we interpret this as a variant of uncertain significance. PM2; PP3 (less)
Indication for testing: Family history of breast cancer
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Uncertain significance
(Feb 07, 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: SCV002532712.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The TP53 c.800G>A (p.R267Q) variant has been reported in heterozygosity in individuals with suspected Li-Fraumeni syndrome (LFS), breast cancer, and adrenocortical carcinoma (PMID: 1562462, 17606709, … (more)
The TP53 c.800G>A (p.R267Q) variant has been reported in heterozygosity in individuals with suspected Li-Fraumeni syndrome (LFS), breast cancer, and adrenocortical carcinoma (PMID: 1562462, 17606709, 25584008, 27210295, 33471991). This variant was also identified in individuals from LFS families in whom it co-occurred with other TP53 variants (PMID: 10435620, 30709875). Functional studies indicate that this variant is a partial deficiency allele resulting in decreased transactivation activity compared to the wild type in yeast and human cell lines (PMID: 10435620, 17606709, 21343334, 12826609) and partial growth suppression defect in human cells (PMID: 10435620, 25584008). However, additional functional studies have shown no evidence of a dominant negative effect or loss of function (PMID: 30224644) and an increase of transactivation function (PMID: 25584008). This variant was observed in 2/112540 chromosomes in the Non-Finnish European subpopulation according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID: 127823). In silico tools suggest the impact of the variant on protein function is deleterious. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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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: SCV004017873.1
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
(Jan 17, 2024)
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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: SCV000260755.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 267 of the TP53 protein (p.Arg267Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 267 of the TP53 protein (p.Arg267Gln). This variant is present in population databases (rs587780075, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 1562462, 9667734, 10435620, 17606709, 25584008, 27210295, 30709875; Invitae). ClinVar contains an entry for this variant (Variation ID: 127823). 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 does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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
(Jun 15, 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: SCV004823765.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces arginine with glutamine at codon 267 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on … (more)
This missense variant replaces arginine with glutamine at codon 267 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 this variant to have a partial defect in transcriptional transactivation activity (PMID: 12826609, 17606709, 20407015, 21343334, 25584008), partial to normal function in human cell growth suppression assays (PMID: 10435620, 25584008, 30224644) and normal function in human cell proliferation assays (PMID: 29979965). This variant has been reported in individuals with suspected Li-Fraumeni syndrome (PMID: 9667734, 10435620, 30709875, 27210295), breast cancer (PMID: 1394133, 1562462, 26225655, 28135048, 29875428, 31060593), colorectal cancer (PMID: 27978560), ovarian cancer (PMID: 16229746), lung cancer (PMID: 28843361), and adrenocortical carcinoma (PMID: 25584008) and lymphoma (PMID: 32504211) in the literature. However it has also been found in controls and unaffected family members (PMID: 1562462, 33471991). This variant has been identified in 3/249356 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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Uncertain significance
(Jul 20, 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: SCV000185134.10
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.R267Q variant (also known as c.800G>A) is located in coding exon 7 of the TP53 gene. This alteration results from a G to A … (more)
The p.R267Q variant (also known as c.800G>A) is located in coding exon 7 of the TP53 gene. This alteration results from a G to A substitution at nucleotide position 800. The arginine at codon 267 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been described several times in conjunction with a second TP53 alteration, p.R156H, in patients meeting LFS criteria, or with LFS spectrum tumors (Quesnel et al. Oncogene. 1999 Jul 8;18(27):3970-8; DiNardo CD et al. Clin Lymphoma Myeloma Leuk. 2016 Jul;16(7):417-428.e2; Pearlman R et al. JAMA Oncol. 2017 Apr 1;3(4):464-471; Swaminathan M et al. Cold Spring Harb Mol Case Stud, 2019 02;5:). This alteration was also described in a patient with breast cancer at 49 years of age, and a family history of lung, breast and ovarian cancer, however, the alteration was also identified in a 74 year old unaffected family member (Prosser et al. Br J Cancer. 1992 Apr;65(4):527-8). In addition, this alteration was detected in a child with adrenal cortical carcinoma, as well as the child's unaffected mother (Wasserman JD et al. J Clin Oncol. 2015 Feb 20;33(6):602-9). Yeast based functional studies describe this alteration as having partially functional transactivation capacity with wide ranging values from as low as 16% to greater than 100% of wild type activity for activation of various downstream targets (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol Cancer Res. 2011. 9(3):271-279; Wasserman JD et al. J Clin Oncol. 2015 Feb 20;33(6):602-9). Growth suppression or colony reduction assays show activity similar to wild type (Wasserman JD et al. J Clin Oncol. 2015 Feb 20;33(6):602-9; Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is not destabilizing, and does not impact any known motifs or protein-protein interfaces (Cho Y et al., Science 1994 Jul; 265(5170):346-55). This alteration has been seen numerous times in our laboratory; several times in unaffected individuals, and never in a case of classic Li Fraumeni syndrome. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this variant remains unclear. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554031.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TP53 p.Arg267Gln variant was identified in 16 of 11062 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, lung cancer, adrenocortical carcinoma, … (more)
The TP53 p.Arg267Gln variant was identified in 16 of 11062 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, lung cancer, adrenocortical carcinoma, sarcoma, and/or Li Fraumeni syndrome (DiNardo 2016, Wasserman 2015, Arcand 2008, Petitjean 2007, Rines 1998). The variant was also identified in ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics, Color and Counsyl) and LOVD 3.0 (as affects function, not classified). The variant was identified in control databases in 3 of 249356 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6086 chromosomes (freq: 0.0002) and European (non-Finnish) in 2 of 112540 chromosomes (freq: 0.00002), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.Arg267 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Arg variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional studies on this variant present conflicting results, such as decreased residual activity but increased transactivation in comparison to wild type (Wasserman 2015, Monti 2011, Jordan 2010). Another study suggests that this variant may result in the creation of a new splice acceptor site (Kouidou 2009). The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (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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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 |
Germline variants discovered in lymphoma patients undergoing tumor profiling: a case series. | Scott AJ | Familial cancer | 2021 | PMID: 32504211 |
p53 major hotspot variants are associated with poorer prognostic features in hereditary cancer patients. | Fortuno C | Cancer genetics | 2019 | PMID: 31296311 |
Frequency of pathogenic germline variants in BRCA1, BRCA2, PALB2, CHEK2 and TP53 in ductal carcinoma in situ diagnosed in women under the age of 50 years. | Petridis C | Breast cancer research : BCR | 2019 | PMID: 31060593 |
Hematologic malignancies and Li-Fraumeni syndrome. | Swaminathan M | Cold Spring Harbor molecular case studies | 2019 | PMID: 30709875 |
The impact of variant classification on the clinical management of hereditary cancer syndromes. | Turner SA | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29875428 |
The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
Current review of TP53 pathogenic germline variants in breast cancer patients outside Li-Fraumeni syndrome. | Fortuno C | Human mutation | 2018 | PMID: 30240537 |
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 |
Screening with whole-body magnetic resonance imaging in pediatric subjects with Li-Fraumeni syndrome: A single institution pilot study. | O'Neill AF | Pediatric blood & cancer | 2018 | PMID: 29077256 |
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 |
Germline Mutations in DNA Repair Genes in Lung Adenocarcinoma. | Parry EM | Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer | 2017 | PMID: 28843361 |
Identification of recurrent BRCA1 mutation and its clinical relevance in Chinese Triple-negative breast cancer cohort. | Liu X | Cancer medicine | 2017 | PMID: 28135048 |
Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. | Pearlman R | JAMA oncology | 2017 | PMID: 27978560 |
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 |
TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. | Kadia TM | Cancer | 2016 | PMID: 27463065 |
Genomic Classification and Prognosis in Acute Myeloid Leukemia. | Papaemmanuil E | The New England journal of medicine | 2016 | PMID: 27276561 |
Evaluation of Patients and Families With Concern for Predispositions to Hematologic Malignancies Within the Hereditary Hematologic Malignancy Clinic (HHMC). | DiNardo CD | Clinical lymphoma, myeloma & leukemia | 2016 | PMID: 27210295 |
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 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients. | Kandioler D | EBioMedicine | 2015 | PMID: 26425688 |
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 |
Targeted Resequencing of 30 Genes Improves the Detection of Deleterious Mutations in South Indian Women with Breast and/or Ovarian Cancers. | Rajkumar T | Asian Pacific journal of cancer prevention : APJCP | 2015 | PMID: 26225655 |
Germline TP53 Mutations in Patients With Early-Onset Colorectal Cancer in the Colon Cancer Family Registry. | Yurgelun MB | JAMA oncology | 2015 | PMID: 26086041 |
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 |
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 |
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 |
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 |
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 |
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
Li-Fraumeni and Li-Fraumeni-like syndrome mutations in p53 are associated with exonic methylation and splicing regulatory elements. | Kouidou S | Molecular carcinogenesis | 2009 | PMID: 19367569 |
Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families. | Arcand SL | Breast cancer research and treatment | 2008 | PMID: 17541742 |
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 |
Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
TP53 mutations in ovarian carcinomas from sporadic cases and carriers of two distinct BRCA1 founder mutations; relation to age at diagnosis and survival. | Kringen P | BMC cancer | 2005 | PMID: 16229746 |
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 |
Mutations in the p53 tumor suppressor gene and early onset breast cancer. | Lai H | Cancer biology & therapy | 2002 | PMID: 12170762 |
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 |
Multiple mutations of the p53 gene in human mammary carcinoma. | Meng L | Mutation research | 1999 | PMID: 10606817 |
p53 compound heterozygosity in a severely affected child with Li-Fraumeni syndrome. | Quesnel S | Oncogene | 1999 | PMID: 10435620 |
Comprehensive mutational scanning of the p53 coding region by two-dimensional gene scanning. | Rines RD | Carcinogenesis | 1998 | PMID: 9667734 |
Constitutional p53 mutation in a non-Li-Fraumeni cancer family. | Prosser J | British journal of cancer | 1992 | PMID: 1562462 |
p53 allele losses, mutations and expression in breast cancer and their relationship to clinico-pathological parameters. | Thompson AM | International journal of cancer | 1992 | PMID: 1537617 |
p53 mutations in breast cancer. | Coles C | Cancer research | 1992 | PMID: 1394133 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ca16e21b-853c-433e-88e5-601b2de6c525 | - | - | - | - |
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HelpRecord last updated Jun 17, 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.