This variant is denoted TP53 c.524G>A at the cDNA level and p.Arg175His (R175H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). TP53 Arg175His has been reported in several individuals meeting clinical diagnostic criteria for Li-Fraumeni syndrome or Chompret criteria for TP53 testing (Birch 1994, Kyritsis 1994, McIntyre 1994, Chompret 2000, Bougeard 2001, Malkin 2001, Potzsch 2002, Walsh 2006, Wong 2006, Choong 2012, Melhem-Bertrandt 2012, Zerdoumi 2013, Maxwell 2016, Park 2016, Zerdoumi 2017) and is considered a common hotspot" variant present in diverse cell lines and tumors (Soussi 2014, COSMIC, IARC TP53 Database). Functional studies have consistently found this variant to impact control of cell growth as well as DNA binding and transcriptional activation (Dittmer 1993, Malcikova 2010, Monti 2011, Wasserman 2015), and TP53 Arg175His is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg175His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider TP53 Arg175His to be pathogenic."
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.524G>A (p.Arg175His)
⚠
Previous version
You are looking at a previous version of this record (VCV000012374.13). Please see
the current version.
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(18)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
18
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.524G>A (p.Arg175His)
Variation ID: 12374 Accession: VCV000012374.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.1 17: 7675088 (GRCh38) [ NCBI UCSC ] 17: 7578406 (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 Oct 19, 2014 Dec 12, 2020 Jan 7, 2020 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.524G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg175His missense NM_000546.5:c.524G>A NP_000537.3:p.Arg175His missense NM_001126112.2:c.524G>A NP_001119584.1:p.Arg175His missense NM_001126113.2:c.524G>A NP_001119585.1:p.Arg175His missense NM_001126114.2:c.524G>A NP_001119586.1:p.Arg175His missense NM_001126115.1:c.128G>A NP_001119587.1:p.Arg43His missense NM_001126116.1:c.128G>A NP_001119588.1:p.Arg43His missense NM_001126117.1:c.128G>A NP_001119589.1:p.Arg43His missense NM_001126118.1:c.407G>A NP_001119590.1:p.Arg136His missense NM_001276695.2:c.407G>A NP_001263624.1:p.Arg136His missense NM_001276696.2:c.407G>A NP_001263625.1:p.Arg136His missense NM_001276697.2:c.47G>A NP_001263626.1:p.Arg16His missense NM_001276698.2:c.47G>A NP_001263627.1:p.Arg16His missense NM_001276699.2:c.47G>A NP_001263628.1:p.Arg16His missense NM_001276760.2:c.407G>A NP_001263689.1:p.Arg136His missense NM_001276761.2:c.407G>A NP_001263690.1:p.Arg136His missense NC_000017.11:g.7675088C>T NC_000017.10:g.7578406C>T NG_017013.2:g.17463G>A LRG_321:g.17463G>A LRG_321t1:c.524G>A LRG_321p1:p.Arg175His LRG_321t2:c.524G>A LRG_321:p.Arg175His LRG_321t3:c.524G>A LRG_321p3:p.Arg175His LRG_321t4:c.524G>A LRG_321p4:p.Arg175His LRG_321t5:c.128G>A LRG_321p5:p.Arg43His LRG_321t6:c.128G>A LRG_321p6:p.Arg43His LRG_321t7:c.128G>A LRG_321p7:p.Arg43His LRG_321t8:c.407G>A LRG_321p8:p.Arg136His P04637:p.Arg175His - Protein change
- R175H, R136H, R43H, R16H
- Other names
-
p.R175H:CGC>CAC
- Canonical SPDI
- NC_000017.11:7675087:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
variation affecting protein function; Variation Ontology [ VariO:0003]
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- 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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, single submitter
|
Mar 18, 2016 | RCV000013173.22 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 13, 2018 | RCV000131301.8 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 7, 2020 | RCV000204931.10 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 14, 2018 | RCV000213054.6 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 29, 2016 | RCV000239398.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Jul 14, 2015 | RCV000421746.1 | |
| not provided (1) |
no classification provided
|
Mar 10, 2016 | RCV000428918.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000763419.1 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
Dec 1, 2018 | RCV000785352.1 | |
| Pathogenic (1) |
no assertion criteria provided
|
Apr 30, 2019 | RCV001255668.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001270268.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001270269.1 | |
| click to load more click to collapse | ||||
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Nov 14, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000211798.11
First in ClinVar: Feb 24, 2015 Last updated: Apr 17, 2019 |
Comment:
This variant is denoted TP53 c.524G>A at the cDNA level and p.Arg175His (R175H) at the protein level, and results in the change of an Arginine … (more)
This variant is denoted TP53 c.524G>A at the cDNA level and p.Arg175His (R175H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). TP53 Arg175His has been reported in several individuals meeting clinical diagnostic criteria for Li-Fraumeni syndrome or Chompret criteria for TP53 testing (Birch 1994, Kyritsis 1994, McIntyre 1994, Chompret 2000, Bougeard 2001, Malkin 2001, Potzsch 2002, Walsh 2006, Wong 2006, Choong 2012, Melhem-Bertrandt 2012, Zerdoumi 2013, Maxwell 2016, Park 2016, Zerdoumi 2017) and is considered a common hotspot" variant present in diverse cell lines and tumors (Soussi 2014, COSMIC, IARC TP53 Database). Functional studies have consistently found this variant to impact control of cell growth as well as DNA binding and transcriptional activation (Dittmer 1993, Malcikova 2010, Monti 2011, Wasserman 2015), and TP53 Arg175His is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg175His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider TP53 Arg175His to be pathogenic." (less)
|
|
|
Pathogenic
(Jul 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine
Accession: SCV000731790.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
The p.Arg175His variant in TP53 has been reported in >16 individuals with Li-Fra umeni syndrome, and segregated with disease in 3 affected relatives from 1 … (more)
The p.Arg175His variant in TP53 has been reported in >16 individuals with Li-Fra umeni syndrome, and segregated with disease in 3 affected relatives from 1 famil y (McIntyre 1994, Varley 1997, Wong 2006, Bougeard 2008, Walsh 2011, Melhem-Bert randt 2012, Park 2016). This variant has also been reported by another clinical laboratory in ClinVar (Variation ID# 12374). In vitro functional studies provide some evidence that the p.Arg175His variant may impact protein function (Kogan-S akin 2011, Grugan 2013) and an in-vivo mouse model has shown that this variant c auses TP53-related tumors (Liu 2010). Additionally, the p.Arg175His variant has been identified in 1/111550 European chromosomes by gnomAD (http://gnomad.broadi nstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg175His variant may impact the protein and 3 other amino acid chang es at this position (Leu, Gly, Cys) have been associated with Li-Fraumeni syndro me (HGMD database; Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manne r based on segregation studies, increased prevalence in affected individuals, ve ry low frequency in controls and functional evidence. ACMG/AMP Criteria applied: PS4, PP1, PS3, PM2. (less)
Number of individuals with the variant: 4
|
|
|
Pathogenic
(Jan 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000261917.8
First in ClinVar: Jan 31, 2016 Last updated: Apr 15, 2020 |
Comment:
This sequence change replaces arginine with histidine at codon 175 of the TP53 protein (p.Arg175His). The arginine residue is highly conserved and there is a … (more)
This sequence change replaces arginine with histidine at codon 175 of the TP53 protein (p.Arg175His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs28934578, ExAC 0.001%). This variant has been observed in individuals and families affected with Li-Fraumeni syndrome, osteosarcoma, breast cancer and ovarian carcinoma (PMID: 8825920, 8164043, 21761402, 22006311, 16401470). ClinVar contains an entry for this variant (Variation ID: 12374). This is a well-studied variant, located in a known mutation hotspot within the central DNA-binding domain of TP53 (PMID: 23263379, 20516128, 24573247, 12007217). It causes not only loss of the tumor suppressor function of the TP53 protein, but also oncogenic gain-of-function (PMID: 23792586, 23263379). In addition, a mouse model of Li-Fraumeni syndrome was engineered using this missense variant (PMID: 15607980, 15607981), and these mice developed a variety of carcinomas and reproduced the metastatic phenotype. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186273.7
First in ClinVar: Aug 06, 2014 Last updated: May 19, 2019 |
Comment:
The p.R175H pathogenic mutation (also known as c.524G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at … (more)
The p.R175H pathogenic mutation (also known as c.524G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 524. This changes the amino acid from an arginine to a histidine at codon 175. This alteration occurs at a well-characterized mutation "hotspot" in the functionally critical DNA binding domain, and is associated with a classic LFS-associated tumor spectrum, including osteosarcomas, rhabdomyosarcomas, early onset colon cancer, breast cancer, and pediatric adrenal cortical tumors (McIntyre JF et al. J. Clin. Oncol. 1994 May;12(5):925-930; Varley JM et al. J. Med. Genet. 1995 Dec;32:942-945; Wong P et al. Gastroenterology. 2006 Jan;130:73-79; Hwang SM et al. Korean J. Lab Med. 2008 Dec;28(6):493-497; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Choong SS et al. Clin. Genet. 2012 Dec;82(6):564-8; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Park KJ et al. Ann. Lab. Med. 2016 Sep;36:463-8; Dudley B et al. Cancer. 2018 Apr;124(8):1691-1700). Functional studies have shown that this alteration leads to an increase in cell colony growth and classified it as a severe transactivation deficiency allele with less than 25% residual protein activity compared to wildtype alleles (Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-279; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9; Wasserman JD et al. J. Clin. Oncol. 2015 Feb;33(6):602-9; Zerdoumi Y et al. Hum. Mol. Genet. 2017 07;26(14):2812). Based on the available evidence, this alteration is classified as a pathogenic mutation. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000488375.1
First in ClinVar: Sep 04, 2016 Last updated: Sep 04, 2016 |
|
|
|
Pathogenic
(Apr 17, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics,PreventionGenetics
Accession: SCV000806241.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
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 Osteosarcoma Carcinoma of pancreas Choroid plexus papilloma Nasopharyngeal carcinoma Basal cell carcinoma, susceptibility to, 7
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics,Fulgent Genetics
Accession: SCV000894156.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Apr 15, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Health, Inc
Accession: SCV000905051.1
First in ClinVar: May 19, 2019 Last updated: May 19, 2019 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: case-control
|
Squamous cell carcinoma of the head and neck
Affected status: yes
Allele origin:
somatic
|
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo
Accession: SCV001450483.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Age: 50-59 years
Sex: male
Geographic origin: Sri Lanka
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: case-control
|
Colorectal cancer
Affected status: yes
Allele origin:
somatic
|
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo
Accession: SCV001450484.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Age: 60-69 years
Sex: male
Geographic origin: Sri Lanka
|
|
|
Likely pathogenic
(Dec 01, 2018)
|
no assertion criteria provided
Method: research
|
Neoplasm of ovary
Affected status: yes
Allele origin:
somatic
|
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne
Accession: SCV000923920.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
|
|
|
Pathogenic
(Aug 01, 2005)
|
no assertion criteria provided
Method: literature only
|
LI-FRAUMENI SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033420.4
First in ClinVar: Apr 04, 2013 Last updated: Jul 13, 2019 |
Comment on evidence:
Varley et al. (1995) studied an extensively affected 4-generation family with Li-Fraumeni syndrome-1 (151623). The structure of the family was sufficient to establish linkage to … (more)
Varley et al. (1995) studied an extensively affected 4-generation family with Li-Fraumeni syndrome-1 (151623). The structure of the family was sufficient to establish linkage to TP53. Subsequent DNA sequence analysis showed a CGC-to-CAC transition in exon 5 of the TP53 gene, resulting in an arg175-to-his (R175H) substitution that altered a recognition site for the restriction enzyme HhaI. This LFS family was unusual for the presence of 2 gastric carcinomas; endometrial cancers were absent, and malignancies were of early onset and particularly severe. Two persons developed a childhood sarcoma, and brain tumors were present in 4. An increase in the risk of breast cancer in mothers of children with osteosarcoma and chondrosarcoma had been reported and was a phenomenon not demonstrated in this family. By in vitro studies, Capponcelli et al. (2005) found that R175H fibroblasts showed increased resistance to doxorubicin treatment with decreased nuclear localization of the p53 protein compared with wildtype cells. (less)
|
|
|
Pathogenic
(Jul 24, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
germline
|
Pathway Genomics
Accession: SCV000189994.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
|
|
|
Pathogenic
(Jul 29, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Esophageal cancer
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo
Accession: SCV000297733.1
First in ClinVar: Aug 13, 2016 Last updated: Aug 13, 2016 |
Comment:
SIFT:Deleterious (score: 0) MutationTaster:Disease causing (p-value: 1)
Age: 50-59 years
Sex: female
Ethnicity/Population group: Sri Lanka/Sinhalese
Geographic origin: Sri Lanka
|
|
|
Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504891.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic
Accession: SCV000692083.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
|
|
Pathogenic
(Apr 30, 2019)
|
no assertion criteria provided
Method: research
|
Lip and oral cavity carcinoma
Affected status: yes
Allele origin:
somatic
|
Institute of Medical Sciences, Banaras Hindu University
Accession: SCV001432233.1
First in ClinVar: Sep 18, 2020 Last updated: Sep 18, 2020 |
|
|
|
not provided
(Mar 10, 2016)
|
no classification provided
Method: literature only
|
Breast neoplasm
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504892.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
The p.Arg175His variant in TP53 has been reported in >16 individuals with Li-Fra umeni syndrome, and segregated with disease in 3 affected relatives from 1 famil y (McIntyre 1994, Varley 1997, Wong 2006, Bougeard 2008, Walsh 2011, Melhem-Bert randt 2012, Park 2016). This variant has also been reported by another clinical laboratory in ClinVar (Variation ID# 12374). In vitro functional studies provide some evidence that the p.Arg175His variant may impact protein function (Kogan-S akin 2011, Grugan 2013) and an in-vivo mouse model has shown that this variant c auses TP53-related tumors (Liu 2010). Additionally, the p.Arg175His variant has been identified in 1/111550 European chromosomes by gnomAD (http://gnomad.broadi nstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg175His variant may impact the protein and 3 other amino acid chang es at this position (Leu, Gly, Cys) have been associated with Li-Fraumeni syndro me (HGMD database; Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manne r based on segregation studies, increased prevalence in affected individuals, ve ry low frequency in controls and functional evidence. ACMG/AMP Criteria applied: PS4, PP1, PS3, PM2.
Comment:
This sequence change replaces arginine with histidine at codon 175 of the TP53 protein (p.Arg175His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs28934578, ExAC 0.001%). This variant has been observed in individuals and families affected with Li-Fraumeni syndrome, osteosarcoma, breast cancer and ovarian carcinoma (PMID: 8825920, 8164043, 21761402, 22006311, 16401470). ClinVar contains an entry for this variant (Variation ID: 12374). This is a well-studied variant, located in a known mutation hotspot within the central DNA-binding domain of TP53 (PMID: 23263379, 20516128, 24573247, 12007217). It causes not only loss of the tumor suppressor function of the TP53 protein, but also oncogenic gain-of-function (PMID: 23792586, 23263379). In addition, a mouse model of Li-Fraumeni syndrome was engineered using this missense variant (PMID: 15607980, 15607981), and these mice developed a variety of carcinomas and reproduced the metastatic phenotype. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R175H pathogenic mutation (also known as c.524G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 524. This changes the amino acid from an arginine to a histidine at codon 175. This alteration occurs at a well-characterized mutation "hotspot" in the functionally critical DNA binding domain, and is associated with a classic LFS-associated tumor spectrum, including osteosarcomas, rhabdomyosarcomas, early onset colon cancer, breast cancer, and pediatric adrenal cortical tumors (McIntyre JF et al. J. Clin. Oncol. 1994 May;12(5):925-930; Varley JM et al. J. Med. Genet. 1995 Dec;32:942-945; Wong P et al. Gastroenterology. 2006 Jan;130:73-79; Hwang SM et al. Korean J. Lab Med. 2008 Dec;28(6):493-497; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Choong SS et al. Clin. Genet. 2012 Dec;82(6):564-8; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Park KJ et al. Ann. Lab. Med. 2016 Sep;36:463-8; Dudley B et al. Cancer. 2018 Apr;124(8):1691-1700). Functional studies have shown that this alteration leads to an increase in cell colony growth and classified it as a severe transactivation deficiency allele with less than 25% residual protein activity compared to wildtype alleles (Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-279; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9; Wasserman JD et al. J. Clin. Oncol. 2015 Feb;33(6):602-9; Zerdoumi Y et al. Hum. Mol. Genet. 2017 07;26(14):2812). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Comment:
SIFT:Deleterious (score: 0) MutationTaster:Disease causing (p-value: 1)
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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variation affecting protein function
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Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo
Accession: SCV000297733.1
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Comment:
This variant is denoted TP53 c.524G>A at the cDNA level and p.Arg175His (R175H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). TP53 Arg175His has been reported in several individuals meeting clinical diagnostic criteria for Li-Fraumeni syndrome or Chompret criteria for TP53 testing (Birch 1994, Kyritsis 1994, McIntyre 1994, Chompret 2000, Bougeard 2001, Malkin 2001, Potzsch 2002, Walsh 2006, Wong 2006, Choong 2012, Melhem-Bertrandt 2012, Zerdoumi 2013, Maxwell 2016, Park 2016, Zerdoumi 2017) and is considered a common hotspot" variant present in diverse cell lines and tumors (Soussi 2014, COSMIC, IARC TP53 Database). Functional studies have consistently found this variant to impact control of cell growth as well as DNA binding and transcriptional activation (Dittmer 1993, Malcikova 2010, Monti 2011, Wasserman 2015), and TP53 Arg175His is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg175His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider TP53 Arg175His to be pathogenic."
Comment:
The p.Arg175His variant in TP53 has been reported in >16 individuals with Li-Fra umeni syndrome, and segregated with disease in 3 affected relatives from 1 famil y (McIntyre 1994, Varley 1997, Wong 2006, Bougeard 2008, Walsh 2011, Melhem-Bert randt 2012, Park 2016). This variant has also been reported by another clinical laboratory in ClinVar (Variation ID# 12374). In vitro functional studies provide some evidence that the p.Arg175His variant may impact protein function (Kogan-S akin 2011, Grugan 2013) and an in-vivo mouse model has shown that this variant c auses TP53-related tumors (Liu 2010). Additionally, the p.Arg175His variant has been identified in 1/111550 European chromosomes by gnomAD (http://gnomad.broadi nstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg175His variant may impact the protein and 3 other amino acid chang es at this position (Leu, Gly, Cys) have been associated with Li-Fraumeni syndro me (HGMD database; Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manne r based on segregation studies, increased prevalence in affected individuals, ve ry low frequency in controls and functional evidence. ACMG/AMP Criteria applied: PS4, PP1, PS3, PM2.
Comment:
This sequence change replaces arginine with histidine at codon 175 of the TP53 protein (p.Arg175His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs28934578, ExAC 0.001%). This variant has been observed in individuals and families affected with Li-Fraumeni syndrome, osteosarcoma, breast cancer and ovarian carcinoma (PMID: 8825920, 8164043, 21761402, 22006311, 16401470). ClinVar contains an entry for this variant (Variation ID: 12374). This is a well-studied variant, located in a known mutation hotspot within the central DNA-binding domain of TP53 (PMID: 23263379, 20516128, 24573247, 12007217). It causes not only loss of the tumor suppressor function of the TP53 protein, but also oncogenic gain-of-function (PMID: 23792586, 23263379). In addition, a mouse model of Li-Fraumeni syndrome was engineered using this missense variant (PMID: 15607980, 15607981), and these mice developed a variety of carcinomas and reproduced the metastatic phenotype. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R175H pathogenic mutation (also known as c.524G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 524. This changes the amino acid from an arginine to a histidine at codon 175. This alteration occurs at a well-characterized mutation "hotspot" in the functionally critical DNA binding domain, and is associated with a classic LFS-associated tumor spectrum, including osteosarcomas, rhabdomyosarcomas, early onset colon cancer, breast cancer, and pediatric adrenal cortical tumors (McIntyre JF et al. J. Clin. Oncol. 1994 May;12(5):925-930; Varley JM et al. J. Med. Genet. 1995 Dec;32:942-945; Wong P et al. Gastroenterology. 2006 Jan;130:73-79; Hwang SM et al. Korean J. Lab Med. 2008 Dec;28(6):493-497; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Choong SS et al. Clin. Genet. 2012 Dec;82(6):564-8; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Park KJ et al. Ann. Lab. Med. 2016 Sep;36:463-8; Dudley B et al. Cancer. 2018 Apr;124(8):1691-1700). Functional studies have shown that this alteration leads to an increase in cell colony growth and classified it as a severe transactivation deficiency allele with less than 25% residual protein activity compared to wildtype alleles (Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-279; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9; Wasserman JD et al. J. Clin. Oncol. 2015 Feb;33(6):602-9; Zerdoumi Y et al. Hum. Mol. Genet. 2017 07;26(14):2812). Based on the available evidence, this alteration is classified as a pathogenic mutation.
Comment:
SIFT:Deleterious (score: 0) MutationTaster:Disease causing (p-value: 1)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Pattern of nucleotide variants of TP53 and their correlation with the expression of p53 and its downstream proteins in a Sri Lankan cohort of breast and colorectal cancer patients. | Manoharan V | BMC cancer | 2020 | PMID: 32000721 |
| Nucleotide variants and protein expression of TP53 in a Sri Lankan cohort of patients with head and neck cancer. | Manoharan V | Molecular medicine reports | 2019 | PMID: 30816478 |
| Hematologic malignancies and Li-Fraumeni syndrome. | Swaminathan M | Cold Spring Harbor molecular case studies | 2019 | PMID: 30709875 |
| The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. | Stenson PD | Human genetics | 2017 | PMID: 28349240 |
| Multiple primary tumors in a family with Li-Fraumeni syndrome with a TP53 germline mutation identified by next-generation sequencing. | Zampiga V | The International journal of biological markers | 2016 | PMID: 27516001 |
| Germline TP53 Mutation and Clinical Characteristics of Korean Patients With Li-Fraumeni Syndrome. | Park KJ | Annals of laboratory medicine | 2016 | PMID: 27374712 |
| Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Heterogeneity of Li-Fraumeni syndrome links to unequal gain-of-function effects of p53 mutations. | Xu J | Scientific reports | 2014 | PMID: 24573247 |
| A common p53 mutation (R175H) activates c-Met receptor tyrosine kinase to enhance tumor cell invasion. | Grugan KD | Cancer biology & therapy | 2013 | PMID: 23792586 |
| p53 mutations in cancer. | Muller PA | Nature cell biology | 2013 | PMID: 23263379 |
| The TP53 website: an integrative resource centre for the TP53 mutation database and TP53 mutant analysis. | Leroy B | Nucleic acids research | 2013 | PMID: 23161690 |
| p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. | Jackson JG | Cancer cell | 2012 | PMID: 22698404 |
| Childhood adrenocortical carcinoma as a sentinel cancer for detecting families with germline TP53 mutations. | Choong SS | Clinical genetics | 2012 | PMID: 22233476 |
| Early onset HER2-positive breast cancer is associated with germline TP53 mutations. | Melhem-Bertrandt A | Cancer | 2012 | PMID: 21761402 |
| Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. | Walsh T | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 22006311 |
| Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
| Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome. | Wu CC | Human genetics | 2011 | PMID: 21305319 |
| Mutant p53(R175H) upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells. | Kogan-Sakin I | Cell death and differentiation | 2011 | PMID: 20689556 |
| The tumor suppressor p53: from structures to drug discovery. | Joerger AC | Cold Spring Harbor perspectives in biology | 2010 | PMID: 20516128 |
| Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. | Malcikova J | Biological chemistry | 2010 | PMID: 20128691 |
| A common gain of function of p53 cancer mutants in inducing genetic instability. | Liu DP | Oncogene | 2010 | PMID: 19881536 |
| Genetic counseling can influence the course of a suspected familial cancer syndrome patient: from a case of Li-Fraumeni like syndrome with a germline mutation in the TP53 gene. | Hwang SM | The Korean journal of laboratory medicine | 2008 | PMID: 19127115 |
| Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. | Bougeard G | Journal of medical genetics | 2008 | PMID: 18511570 |
| p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. | Kawauchi K | Nature cell biology | 2008 | PMID: 18391940 |
| 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 |
| The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. | Olivier M | Clinical cancer research : an official journal of the American Association for Cancer Research | 2006 | PMID: 16489069 |
| Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. | Wong P | Gastroenterology | 2006 | PMID: 16401470 |
| Evaluation of the molecular mechanisms involved in the gain of function of a Li-Fraumeni TP53 mutation. | Capponcelli S | Human mutation | 2005 | PMID: 15977174 |
| Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. | Lang GA | Cell | 2004 | PMID: 15607981 |
| Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. | Olive KP | Cell | 2004 | PMID: 15607980 |
| 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 |
| Germline TP53 mutations and Li-Fraumeni syndrome. | Varley JM | Human mutation | 2003 | PMID: 12619118 |
| The IARC TP53 database: new online mutation analysis and recommendations to users. | Olivier M | Human mutation | 2002 | PMID: 12007217 |
| Role of the p53-homologue p73 in E2F1-induced apoptosis. | Stiewe T | Nature genetics | 2000 | PMID: 11101847 |
| A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li-Fraumeni patients carrying a mutation to the TP53 gene. | Varley JM | Oncogene | 1997 | PMID: 9047394 |
| An extended Li-Fraumeni kindred with gastric carcinoma and a codon 175 mutation in TP53. | Varley JM | Journal of medical genetics | 1995 | PMID: 8825920 |
| Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. | McIntyre JF | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 1994 | PMID: 8164043 |
| http://docm.genome.wustl.edu/variants/ENST00000269305:c.524G>A | - | - | - | - |
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Text-mined citations for rs28934578 ...
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Record last updated May 24, 2021
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.