The NM_000546.6: c.847C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 283(p.Arg283Cys). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000183772.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.33; Align GVGD = Class 55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant (c.848G>C, p.Arg283Pro) (ClinVar Variation ID: 486555), in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni Syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, PP3, PM5_Supporting. (Bayesian Points: -6; VCEP specifications version 2.0; 7/24/2024)
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.847C>T (p.Arg283Cys)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Likely Benign
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.847C>T (p.Arg283Cys)
Variation ID: 127824 Accession: VCV000127824.68
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.1 17: 7673773 (GRCh38) [ NCBI UCSC ] 17: 7577091 (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 Jun 9, 2014 Oct 20, 2024 Aug 5, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.847C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg283Cys missense NM_000546.5(TP53):c.847C>T NM_001126112.3:c.847C>T NP_001119584.1:p.Arg283Cys missense NM_001126113.3:c.847C>T NP_001119585.1:p.Arg283Cys missense NM_001126114.3:c.847C>T NP_001119586.1:p.Arg283Cys missense NM_001126115.2:c.451C>T NP_001119587.1:p.Arg151Cys missense NM_001126116.2:c.451C>T NP_001119588.1:p.Arg151Cys missense NM_001126117.2:c.451C>T NP_001119589.1:p.Arg151Cys missense NM_001126118.2:c.730C>T NP_001119590.1:p.Arg244Cys missense NM_001276695.3:c.730C>T NP_001263624.1:p.Arg244Cys missense NM_001276696.3:c.730C>T NP_001263625.1:p.Arg244Cys missense NM_001276697.3:c.370C>T NP_001263626.1:p.Arg124Cys missense NM_001276698.3:c.370C>T NP_001263627.1:p.Arg124Cys missense NM_001276699.3:c.370C>T NP_001263628.1:p.Arg124Cys missense NM_001276760.3:c.730C>T NP_001263689.1:p.Arg244Cys missense NM_001276761.3:c.730C>T NP_001263690.1:p.Arg244Cys missense NC_000017.11:g.7673773G>A NC_000017.10:g.7577091G>A NG_017013.2:g.18778C>T LRG_321:g.18778C>T LRG_321t1:c.847C>T LRG_321p1:p.Arg283Cys LRG_321t2:c.847C>T LRG_321:p.Arg283Cys LRG_321t3:c.847C>T LRG_321p3:p.Arg283Cys P04637:p.Arg283Cys - Protein change
- R151C, R244C, R283C, R124C
- Other names
-
p.R283C:CGC>TGC
- Canonical SPDI
- NC_000017.11:7673772:G:A
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
Trans-Omics for Precision Medicine (TOPMed) 0.00007
The Genome Aggregation Database (gnomAD) 0.00009
- 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 |
3367 | 3466 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Mar 5, 2024 | RCV000115739.31 | |
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Feb 6, 2024 | RCV000122178.23 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jun 1, 2014 | RCV000148912.11 | |
| Likely benign (3) |
reviewed by expert panel
|
Aug 5, 2024 | RCV000200641.33 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2019 | RCV000238755.11 | |
| Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Jun 22, 2023 | RCV000585912.39 | |
| Likely benign (1) |
criteria provided, single submitter
|
May 17, 2022 | RCV002477279.8 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001357872.9 |
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. |
|
|---|---|---|---|---|---|
|
Likely Benign
(Aug 05, 2024)
|
reviewed by expert panel
Method: curation
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen TP53 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV001142525.3 First in ClinVar: Jan 12, 2020 Last updated: Aug 18, 2024 |
Comment:
The NM_000546.6: c.847C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 283(p.Arg283Cys). This variant has … (more)
The NM_000546.6: c.847C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 283(p.Arg283Cys). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000183772.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.33; Align GVGD = Class 55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant (c.848G>C, p.Arg283Pro) (ClinVar Variation ID: 486555), in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni Syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, PP3, PM5_Supporting. (Bayesian Points: -6; VCEP specifications version 2.0; 7/24/2024) (less)
|
|
|
Uncertain significance
(Aug 06, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002532714.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The TP53 c.847C>T (p.R283C) variant has been reported in heterozygosity in multiple individuals with sarcoma, breast cancer, ovarian cancer, glioblastoma, and other cancers (PMID: 15173255, … (more)
The TP53 c.847C>T (p.R283C) variant has been reported in heterozygosity in multiple individuals with sarcoma, breast cancer, ovarian cancer, glioblastoma, and other cancers (PMID: 15173255, 31749828, 17224268, 19714488, 31159747). This variant has also been reported in healthy individuals (PMID: 24728327, 25637381, 28861920). The three main functional studies as recommended by the ClinGen Expert Panel (PMID: 12826609, 30224644, 29979965) all suggest the variant does not impact the normal function of the protein, though at least one study showed a decreased protein activity caused by this variant (PMID: 21343334). This variant involves a moderately conserved amino acid, and computational analyses suggest that the variant does not impact the function of protein. This variant was observed in 17/129154 chromosomes in the European (non-Finnish) subpopulation, with no homozygotes, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654) and has been reported in ClinVar (Variation ID: 127824). The overall evidence is inconsistent with ACMG/AMP requirements for a classification of benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
|
|
|
|
Uncertain significance
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440887.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
|
|
|
Likely benign
(May 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Colorectal cancer Hepatocellular carcinoma Glioma susceptibility 1 Li-Fraumeni syndrome 1 Adrenocortical carcinoma, hereditary Bone osteosarcoma Familial pancreatic carcinoma Choroid plexus papilloma Nasopharyngeal carcinoma Basal cell carcinoma, susceptibility to, 7 Bone marrow failure syndrome 5
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000896672.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
|
Likely benign
(Oct 27, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149648.16
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 22652532, 19367569, 17289876, 25527155, 21343334, no PMID, 15173255, 30224644, 29979965, 31016814, 23018556, 22710932, 17224268, 25980754, 23894400, … (more)
This variant is associated with the following publications: (PMID: 22652532, 19367569, 17289876, 25527155, 21343334, no PMID, 15173255, 30224644, 29979965, 31016814, 23018556, 22710932, 17224268, 25980754, 23894400, 24728327, 21288114, 21512767, 25637381, 19558493, 21232794, 16487937, 19714488, 11040944, 26086041, 24868540, 12826609, 11793474, 8198984, 9865903, 11391594, 17727479, 28125078, 28861920, 15580553, 8203469, 29785153, 29300620, 21761402, 30840781, 31159747, 30374176, 29945567, 31786208, 31749828, 33300245, 32658383) (less)
|
|
|
Likely benign
(Feb 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004242756.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
|
Likely benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254640.13
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
|
|
|
Likely benign
(Sep 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000183772.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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)
|
|
|
Uncertain significance
(Mar 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV005045436.1
First in ClinVar: May 26, 2024 Last updated: May 26, 2024 |
|
|
|
Uncertain significance
(Apr 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000597522.1
First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017 |
|
|
|
Uncertain significance
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000822209.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
|
|
|
Uncertain significance
(Nov 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697452.2
First in ClinVar: Mar 17, 2018 Last updated: Jun 22, 2020 |
Comment:
Variant summary: TP53 c.847C>T (p.Arg283Cys) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Four of … (more)
Variant summary: TP53 c.847C>T (p.Arg283Cys) results in a non-conservative amino acid change located in the 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 7.2e-05 in 251440 control chromosomes (gnomAD). The observed variant frequency is approximately 2-folds over the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome (LFS) phenotype (4e-05), strongly suggesting that the variant is benign. c.847C>T has been reported in the literature in patients with CLL, early-onset colorectal cancer, breast cancer, gastric carcinoma, pancreatic, and brain tumor as a germline or somatic variant, but most of the patients did not fulfill LFS criteria (e.g. Gaidano_1994, Yurgelun_2015, Manoukian_2007, Keller_2004, Melhem-Bertrandt_2012, Mitchell_2013, Schulz_2012, Wang_2013, Abe_2019, Mai_2017, Momozawa_2018, Tsaousis_2019, Young_2018). In addition, one patient who was affected with metachronous breast cancers and a subsequent leiomyosarcoma carried TP53 c.847C>T variant and a pathogenic BRCA2 variant (p.Arg2394X); however TP53 c.847C>T did not segregate with disease in her family, as it was absent in an astrocytoma patient (Manoukian_2007). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Functional studies provide conflicting results ranging from no defect (human cell line) to partially defective in yeasts (Pekova_2011, Monti_2011, Jagosova_2012). In addition, the IARC database indicates the variant to be functional. Twelve ClinVar submissions (evaluation after 2014) cite the variant eleven times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. (less)
|
|
|
Uncertain significance
(Jan 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000272533.4
First in ClinVar: Jun 09, 2014 Last updated: Jul 06, 2020 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg283Cys variant in TP53 has been reported in multiple individuals with cancer who did not meet … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg283Cys variant in TP53 has been reported in multiple individuals with cancer who did not meet Li-Fraumeni diagnostic criteria, and as a somatic variant in at least 7 tumors (Faille 1994, Diller 1995, Rugge 2000, Prescott 2001, Keller 2004, Libe 2007, Manoukian 2007, Ryu 2007, Pekova 2011, Melhem-Bertandt 2012, Schulz 2012, Boyault 2012, Mitchell 2013, Yurgelun 2015, Brohl 2017). It has also been identified in 17/129154 European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, though in vitro functional studies provide some evidence that the p.Arg283Cys variant may impact protein function (Monti 2011, Pekova 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg283Cys variant is uncertain. (less)
Number of individuals with the variant: 2
|
|
|
Uncertain significance
(Mar 28, 2018)
|
criteria provided, single submitter
Method: research
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000886456.2
First in ClinVar: Feb 23, 2019 Last updated: Dec 07, 2020 |
Comment:
The TP53 variant designated as NM_000546.5:c.847C>T (p.Arg283Cys) is classified as unlikely to cause fully penetrant Li-Fraumeni syndrome. Cosegregation analysis of one observed family was performed … (more)
The TP53 variant designated as NM_000546.5:c.847C>T (p.Arg283Cys) is classified as unlikely to cause fully penetrant Li-Fraumeni syndrome. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of less than 0.005 to 1 (Thompson et al., 2013, PMID:12900794) in the context of Li-Fraumeni syndrome. This indicates that the TP53 variant is very unlikely to increase the risks of cancer to the extent reported in Li-Fraumeni syndrome. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity in the context of Li-Fraumeni syndrome. Additionally, the familial germline TP53 variant was detected in a family member's breast tumor tissue without evidence of loss of heterozygosity. It was unclear whether there was a second hit. The absence of loss of heterozygosity in the tumor may provide some evidence that the TP53 variant is more likely to be benign. There have been many reports this variant in patients with cancer. Although it is clear that this variant does not cause classic Li-Fraumeni syndrome, we cannot rule out the possibility that this variant does cause some increased risk for breast and other cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. (less)
Family history: yes
|
|
|
Uncertain significance
(Aug 19, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000297015.3
First in ClinVar: Jul 31, 2016 Last updated: Dec 24, 2022 |
|
|
|
Likely benign
(Jun 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889883.3
First in ClinVar: Mar 17, 2018 Last updated: Jan 06, 2024 |
|
|
|
Likely benign
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000686778.6
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
|
|
|
Likely benign
(Jan 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV000892470.28
First in ClinVar: Mar 31, 2019 Last updated: Oct 20, 2024 |
Comment:
TP53: PP3, PS4:Supporting, BS3:Supporting, BS2
Number of individuals with the variant: 6
|
|
|
Likely pathogenic
(Jun 01, 2014)
|
no assertion criteria provided
Method: research
|
Gastric cancer
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190658.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
|
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001553463.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TP53 p.Arg283Cys variant was identified in 14 of 16242 proband chromosomes (frequency: 0.0009) from individuals or families with gastric cancer, breast cancer, leiomyosarcoma, sarcoma, … (more)
The TP53 p.Arg283Cys variant was identified in 14 of 16242 proband chromosomes (frequency: 0.0009) from individuals or families with gastric cancer, breast cancer, leiomyosarcoma, sarcoma, or colorectal cancer and was present in 2 of 23844 control chromosomes (frequency: 0.00008) from healthy individuals (Keller 2004, Manoukian 2007, Mitchell 2013, Momozawa 2018, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs149633775) as "With Likely pathogenic allele", ClinVar (classified as likely benign by one submitter; as uncertain significance by Invitae, GeneDx, Ambry Genetics and six other submitters; and as likely pathogenic by one submitter), Cosmic (22x in breast, endometrium, pancreatic and other tissues ), and LOVD 3.0 (3x). The variant was identified in control databases in 24 of 277184 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The frequency of the variant in certain populations increases the likelihood that this is a low frequency, benign variant; it was observed in the following populations: African in 3 of 24034 chromosomes (freq: 0.0001), Other in 1 of 6466 chromosomes (freq: 0.0002), and European in 20 of 126682 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vitro studies of the variant provide conflicting data: the variant demonstrated weakly temperature-dependent activity, partial deficiency of activity, or activity similar to wild type (Jagosove 2012, Pekova 2011, Monti 2011). The variant was identified in a family meeting criteria for HBOC and Li Fraumeni-like syndrome along with a pathogenic BRCA2 variant (c.7408A>T, p.R2394X). The p.Arg283 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing. 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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not provided
(-)
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no classification provided
Method: phenotyping only
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Not Provided
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001716320.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
Variant interpreted as Uncertain significance and reported on 08-08-2017 by 1197. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Uncertain significance and reported on 08-08-2017 by 1197. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. (less)
Clinical Features:
Myopia (present) , Asthma (present) , Abnormal intestine morphology (present) , Abnormal delivery (present)
Indication for testing: Presymptomatic
Age: 30-39 years
Sex: female
Ethnicity/Population group: Caucasians
Testing laboratory: Myriad Genetic Laboratories, Inc.,Myriad Genetic Laboratories, Inc.
Date variant was reported to submitter: 2017-08-08
Testing laboratory interpretation: Uncertain significance
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not provided
(Sep 19, 2013)
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no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
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ITMI
Accession: SCV000086393.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
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Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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Comment:
Comment:
This variant is associated with the following publications: (PMID: 22652532, 19367569, 17289876, 25527155, 21343334, no PMID, 15173255, 30224644, 29979965, 31016814, 23018556, 22710932, 17224268, 25980754, 23894400, 24728327, 21288114, 21512767, 25637381, 19558493, 21232794, 16487937, 19714488, 11040944, 26086041, 24868540, 12826609, 11793474, 8198984, 9865903, 11391594, 17727479, 28125078, 28861920, 15580553, 8203469, 29785153, 29300620, 21761402, 30840781, 31159747, 30374176, 29945567, 31786208, 31749828, 33300245, 32658383)
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Comment:
Variant summary: TP53 c.847C>T (p.Arg283Cys) results in a non-conservative amino acid change located in the 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 7.2e-05 in 251440 control chromosomes (gnomAD). The observed variant frequency is approximately 2-folds over the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome (LFS) phenotype (4e-05), strongly suggesting that the variant is benign. c.847C>T has been reported in the literature in patients with CLL, early-onset colorectal cancer, breast cancer, gastric carcinoma, pancreatic, and brain tumor as a germline or somatic variant, but most of the patients did not fulfill LFS criteria (e.g. Gaidano_1994, Yurgelun_2015, Manoukian_2007, Keller_2004, Melhem-Bertrandt_2012, Mitchell_2013, Schulz_2012, Wang_2013, Abe_2019, Mai_2017, Momozawa_2018, Tsaousis_2019, Young_2018). In addition, one patient who was affected with metachronous breast cancers and a subsequent leiomyosarcoma carried TP53 c.847C>T variant and a pathogenic BRCA2 variant (p.Arg2394X); however TP53 c.847C>T did not segregate with disease in her family, as it was absent in an astrocytoma patient (Manoukian_2007). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Functional studies provide conflicting results ranging from no defect (human cell line) to partially defective in yeasts (Pekova_2011, Monti_2011, Jagosova_2012). In addition, the IARC database indicates the variant to be functional. Twelve ClinVar submissions (evaluation after 2014) cite the variant eleven times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg283Cys variant in TP53 has been reported in multiple individuals with cancer who did not meet Li-Fraumeni diagnostic criteria, and as a somatic variant in at least 7 tumors (Faille 1994, Diller 1995, Rugge 2000, Prescott 2001, Keller 2004, Libe 2007, Manoukian 2007, Ryu 2007, Pekova 2011, Melhem-Bertandt 2012, Schulz 2012, Boyault 2012, Mitchell 2013, Yurgelun 2015, Brohl 2017). It has also been identified in 17/129154 European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, though in vitro functional studies provide some evidence that the p.Arg283Cys variant may impact protein function (Monti 2011, Pekova 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg283Cys variant is uncertain.
Comment:
The TP53 variant designated as NM_000546.5:c.847C>T (p.Arg283Cys) is classified as unlikely to cause fully penetrant Li-Fraumeni syndrome. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of less than 0.005 to 1 (Thompson et al., 2013, PMID:12900794) in the context of Li-Fraumeni syndrome. This indicates that the TP53 variant is very unlikely to increase the risks of cancer to the extent reported in Li-Fraumeni syndrome. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity in the context of Li-Fraumeni syndrome. Additionally, the familial germline TP53 variant was detected in a family member's breast tumor tissue without evidence of loss of heterozygosity. It was unclear whether there was a second hit. The absence of loss of heterozygosity in the tumor may provide some evidence that the TP53 variant is more likely to be benign. There have been many reports this variant in patients with cancer. Although it is clear that this variant does not cause classic Li-Fraumeni syndrome, we cannot rule out the possibility that this variant does cause some increased risk for breast and other cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Comment:
TP53: PP3, PS4:Supporting, BS3:Supporting, BS2
Comment:
The TP53 p.Arg283Cys variant was identified in 14 of 16242 proband chromosomes (frequency: 0.0009) from individuals or families with gastric cancer, breast cancer, leiomyosarcoma, sarcoma, or colorectal cancer and was present in 2 of 23844 control chromosomes (frequency: 0.00008) from healthy individuals (Keller 2004, Manoukian 2007, Mitchell 2013, Momozawa 2018, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs149633775) as "With Likely pathogenic allele", ClinVar (classified as likely benign by one submitter; as uncertain significance by Invitae, GeneDx, Ambry Genetics and six other submitters; and as likely pathogenic by one submitter), Cosmic (22x in breast, endometrium, pancreatic and other tissues ), and LOVD 3.0 (3x). The variant was identified in control databases in 24 of 277184 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The frequency of the variant in certain populations increases the likelihood that this is a low frequency, benign variant; it was observed in the following populations: African in 3 of 24034 chromosomes (freq: 0.0001), Other in 1 of 6466 chromosomes (freq: 0.0002), and European in 20 of 126682 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vitro studies of the variant provide conflicting data: the variant demonstrated weakly temperature-dependent activity, partial deficiency of activity, or activity similar to wild type (Jagosove 2012, Pekova 2011, Monti 2011). The variant was identified in a family meeting criteria for HBOC and Li Fraumeni-like syndrome along with a pathogenic BRCA2 variant (c.7408A>T, p.R2394X). The p.Arg283 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing. 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.
Comment:
Variant interpreted as Uncertain significance and reported on 08-08-2017 by 1197. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory.
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:
The NM_000546.6: c.847C>T variant in TP53 is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 283(p.Arg283Cys). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; SCV000183772.8). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = 0.33; Align GVGD = Class 55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). Another missense variant (c.848G>C, p.Arg283Pro) (ClinVar Variation ID: 486555), in the same codon have been classified as likely pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications.(PM5_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni Syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, BS3, PP3, PM5_Supporting. (Bayesian Points: -6; VCEP specifications version 2.0; 7/24/2024)
Comment:
This variant is associated with the following publications: (PMID: 22652532, 19367569, 17289876, 25527155, 21343334, no PMID, 15173255, 30224644, 29979965, 31016814, 23018556, 22710932, 17224268, 25980754, 23894400, 24728327, 21288114, 21512767, 25637381, 19558493, 21232794, 16487937, 19714488, 11040944, 26086041, 24868540, 12826609, 11793474, 8198984, 9865903, 11391594, 17727479, 28125078, 28861920, 15580553, 8203469, 29785153, 29300620, 21761402, 30840781, 31159747, 30374176, 29945567, 31786208, 31749828, 33300245, 32658383)
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Comment:
Variant summary: TP53 c.847C>T (p.Arg283Cys) results in a non-conservative amino acid change located in the 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 7.2e-05 in 251440 control chromosomes (gnomAD). The observed variant frequency is approximately 2-folds over the estimated maximal expected allele frequency for a pathogenic variant in TP53 causing Li-Fraumeni Syndrome (LFS) phenotype (4e-05), strongly suggesting that the variant is benign. c.847C>T has been reported in the literature in patients with CLL, early-onset colorectal cancer, breast cancer, gastric carcinoma, pancreatic, and brain tumor as a germline or somatic variant, but most of the patients did not fulfill LFS criteria (e.g. Gaidano_1994, Yurgelun_2015, Manoukian_2007, Keller_2004, Melhem-Bertrandt_2012, Mitchell_2013, Schulz_2012, Wang_2013, Abe_2019, Mai_2017, Momozawa_2018, Tsaousis_2019, Young_2018). In addition, one patient who was affected with metachronous breast cancers and a subsequent leiomyosarcoma carried TP53 c.847C>T variant and a pathogenic BRCA2 variant (p.Arg2394X); however TP53 c.847C>T did not segregate with disease in her family, as it was absent in an astrocytoma patient (Manoukian_2007). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Functional studies provide conflicting results ranging from no defect (human cell line) to partially defective in yeasts (Pekova_2011, Monti_2011, Jagosova_2012). In addition, the IARC database indicates the variant to be functional. Twelve ClinVar submissions (evaluation after 2014) cite the variant eleven times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg283Cys variant in TP53 has been reported in multiple individuals with cancer who did not meet Li-Fraumeni diagnostic criteria, and as a somatic variant in at least 7 tumors (Faille 1994, Diller 1995, Rugge 2000, Prescott 2001, Keller 2004, Libe 2007, Manoukian 2007, Ryu 2007, Pekova 2011, Melhem-Bertandt 2012, Schulz 2012, Boyault 2012, Mitchell 2013, Yurgelun 2015, Brohl 2017). It has also been identified in 17/129154 European chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein, though in vitro functional studies provide some evidence that the p.Arg283Cys variant may impact protein function (Monti 2011, Pekova 2011). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg283Cys variant is uncertain.
Comment:
The TP53 variant designated as NM_000546.5:c.847C>T (p.Arg283Cys) is classified as unlikely to cause fully penetrant Li-Fraumeni syndrome. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and gives a likelihood ratio of less than 0.005 to 1 (Thompson et al., 2013, PMID:12900794) in the context of Li-Fraumeni syndrome. This indicates that the TP53 variant is very unlikely to increase the risks of cancer to the extent reported in Li-Fraumeni syndrome. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity in the context of Li-Fraumeni syndrome. Additionally, the familial germline TP53 variant was detected in a family member's breast tumor tissue without evidence of loss of heterozygosity. It was unclear whether there was a second hit. The absence of loss of heterozygosity in the tumor may provide some evidence that the TP53 variant is more likely to be benign. There have been many reports this variant in patients with cancer. Although it is clear that this variant does not cause classic Li-Fraumeni syndrome, we cannot rule out the possibility that this variant does cause some increased risk for breast and other cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Comment:
TP53: PP3, PS4:Supporting, BS3:Supporting, BS2
Comment:
The TP53 p.Arg283Cys variant was identified in 14 of 16242 proband chromosomes (frequency: 0.0009) from individuals or families with gastric cancer, breast cancer, leiomyosarcoma, sarcoma, or colorectal cancer and was present in 2 of 23844 control chromosomes (frequency: 0.00008) from healthy individuals (Keller 2004, Manoukian 2007, Mitchell 2013, Momozawa 2018, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs149633775) as "With Likely pathogenic allele", ClinVar (classified as likely benign by one submitter; as uncertain significance by Invitae, GeneDx, Ambry Genetics and six other submitters; and as likely pathogenic by one submitter), Cosmic (22x in breast, endometrium, pancreatic and other tissues ), and LOVD 3.0 (3x). The variant was identified in control databases in 24 of 277184 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The frequency of the variant in certain populations increases the likelihood that this is a low frequency, benign variant; it was observed in the following populations: African in 3 of 24034 chromosomes (freq: 0.0001), Other in 1 of 6466 chromosomes (freq: 0.0002), and European in 20 of 126682 chromosomes (freq: 0.0002), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vitro studies of the variant provide conflicting data: the variant demonstrated weakly temperature-dependent activity, partial deficiency of activity, or activity similar to wild type (Jagosove 2012, Pekova 2011, Monti 2011). The variant was identified in a family meeting criteria for HBOC and Li Fraumeni-like syndrome along with a pathogenic BRCA2 variant (c.7408A>T, p.R2394X). The p.Arg283 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing. 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.
Comment:
Variant interpreted as Uncertain significance and reported on 08-08-2017 by 1197. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Spectrum of High-Risk Mutations among Breast Cancer Patients Referred for Multigene Panel Testing in a Romanian Population. | Goidescu IG | Cancers | 2023 | PMID: 36980780 |
| Benign SNPs in the Coding Region of TP53: Finding the Needles in a Haystack of Pathogenic Variants. | Soussi T | Cancer research | 2022 | PMID: 35802772 |
| Inherited TP53 Variants and Risk of Prostate Cancer. | Maxwell KN | European urology | 2022 | PMID: 34863587 |
| TP53 mutations determined by targeted NGS in breast cancer: a case-control study. | Andrikopoulou A | Oncotarget | 2021 | PMID: 34676052 |
| Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants. | Fortuno C | Human mutation | 2021 | PMID: 33300245 |
| TP53 germline mutations in the context of families with hereditary breast and ovarian cancer: a clinical challenge. | Grill S | Archives of gynecology and obstetrics | 2021 | PMID: 33245408 |
| A pedigree-based prediction model identifies carriers of deleterious de novo mutations in families with Li-Fraumeni syndrome. | Gao F | Genome research | 2020 | PMID: 32817165 |
| Rhabdomyosarcoma associated with germline TP53 alteration in children and adolescents: The French experience. | Pondrom M | Pediatric blood & cancer | 2020 | PMID: 32658383 |
| Identification of germline pathogenic variants in DNA damage repair genes by a next-generation sequencing multigene panel in BRCAX patients. | Rodríguez-Balada M | Clinical biochemistry | 2020 | PMID: 31786208 |
| A Pediatric Case of Glioblastoma Multiforme Associated With a Novel Germline p.His112CysfsTer9 Mutation in the MLH1 Gene Accompanied by a p.Arg283Cys Mutation in the TP53 Gene: A Case Report. | Stajkovska A | Frontiers in genetics | 2019 | PMID: 31749828 |
| Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. | Tsaousis GN | BMC cancer | 2019 | PMID: 31159747 |
| Concern regarding classification of germline TP53 variants as likely pathogenic. | Evans DG | Human mutation | 2019 | PMID: 31016814 |
| Deleterious Germline Mutations Are a Risk Factor for Neoplastic Progression Among High-Risk Individuals Undergoing Pancreatic Surveillance. | Abe T | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2019 | PMID: 30883245 |
| Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance. | Tsai GJ | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30374176 |
| The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
| Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
| 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 |
| Pancreatic cancer as a sentinel for hereditary cancer predisposition. | Young EL | BMC cancer | 2018 | PMID: 29945567 |
| TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children. | Qian M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2018 | PMID: 29300620 |
| 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 |
| Prevalence of Cancer at Baseline Screening in the National Cancer Institute Li-Fraumeni Syndrome Cohort. | Mai PL | JAMA oncology | 2017 | PMID: 28772286 |
| Frequent inactivating germline mutations in DNA repair genes in patients with Ewing sarcoma. | Brohl AS | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28125078 |
| 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 |
| 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 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 |
| 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 |
| Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
| TP53 mutation analysis in chronic lymphocytic leukemia: comparison of different detection methods. | Kantorova B | Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | 2015 | PMID: 25527155 |
| IDH1/IDH2 but not TP53 mutations predict prognosis in Bulgarian glioblastoma patients. | Stancheva G | BioMed research international | 2014 | PMID: 24868540 |
| Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
| High frequency of germline TP53 mutations in a prospective adult-onset sarcoma cohort. | Mitchell G | PloS one | 2013 | PMID: 23894400 |
| Increased oxidative metabolism in the Li-Fraumeni syndrome. | Wang PY | The New England journal of medicine | 2013 | PMID: 23484829 |
| 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 |
| Transactivation and reactivation capabilities of temperature-dependent p53 mutants in yeast and human cells. | Jagosova J | International journal of oncology | 2012 | PMID: 22710932 |
| Germline mutations in the DNA damage response genes BRCA1, BRCA2, BARD1 and TP53 in patients with therapy related myeloid neoplasms. | Schulz E | Journal of medical genetics | 2012 | PMID: 22652532 |
| 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 |
| Early onset HER2-positive breast cancer is associated with germline TP53 mutations. | Melhem-Bertrandt A | Cancer | 2012 | PMID: 21761402 |
| Mutational characterization of individual breast tumors: TP53 and PI3K pathway genes are frequently and distinctively mutated in different subtypes. | Boyault S | Breast cancer research and treatment | 2012 | PMID: 21512767 |
| 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 |
| A comprehensive study of TP53 mutations in chronic lymphocytic leukemia: Analysis of 1287 diagnostic and 1148 follow-up CLL samples. | Pekova S | Leukemia research | 2011 | PMID: 21232794 |
| Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
| The prevalence of germ-line TP53 mutations in women diagnosed with breast cancer before age 30. | Ginsburg OM | Familial cancer | 2009 | PMID: 19714488 |
| 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 |
| Prognostic significance of p53 gene mutations and protein overexpression in localized gastrointestinal stromal tumours. | Ryu MH | Histopathology | 2007 | PMID: 17727479 |
| 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 |
| Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity. | Libè R | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17289876 |
| Germline mutations of TP53 and BRCA2 genes in breast cancer/sarcoma families. | Manoukian S | European journal of cancer (Oxford, England : 1990) | 2007 | PMID: 17224268 |
| Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
| Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations. | Soussi T | Human mutation | 2005 | PMID: 15580553 |
| Germline mutations of the E-cadherin(CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients. | Keller G | Journal of medical genetics | 2004 | PMID: 15173255 |
| 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 |
| 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 |
| Clinical sensitivity of p53 mutation detection in matched bladder tumor, bladder wash, and voided urine specimens. | Prescott JL | Cancer | 2001 | PMID: 11391594 |
| The p53 gene in patients under the age of 40 with gastric cancer: mutation rates are low but are associated with a cardiac location. | Rugge M | Molecular pathology : MP | 2000 | PMID: 11040944 |
| Comparison of features of human breast cancer cell lines and their corresponding tumors. | Wistuba II | Clinical cancer research : an official journal of the American Association for Cancer Research | 1998 | PMID: 9865903 |
| Analysis of alterations of oncogenes and tumor suppressor genes in chronic lymphocytic leukemia. | Gaidano G | The American journal of pathology | 1994 | PMID: 8203469 |
| p53 mutations and overexpression in locally advanced breast cancers. | Faille A | British journal of cancer | 1994 | PMID: 8198984 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/0b9a7a17-b7b8-4223-bd64-69617a2d691d | - | - | - | - |
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Text-mined citations for rs149633775 ...
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Record last updated Oct 27, 2024
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