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NM_000546.6(TP53):c.524G>A (p.Arg175His)

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Interpretation:
Pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
24 (Most recent: Sep 30, 2021)
Last evaluated:
Jan 4, 2021
Accession:
VCV000012374.21
Variation ID:
12374
Description:
single nucleotide variant
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NM_000546.6(TP53):c.524G>A (p.Arg175His)

Allele ID
27413
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17p13.1
Genomic location
17: 7675088 (GRCh38) GRCh38 UCSC
17: 7578406 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
P04637:p.Arg175His
LRG_321:g.17463G>A
LRG_321t1:c.524G>A LRG_321p1:p.Arg175His
... more HGVS
Protein change
R175H, R136H, R43H, R16H
Other names
p.R175H:CGC>CAC
Canonical SPDI
NC_000017.11:7675087:C:T
Functional consequence
variation affecting protein function [Variation Ontology VariO:0003]
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
Links
ClinGen: CA000251
UniProtKB: P04637#VAR_005932
OMIM: 191170.0030
dbSNP: rs28934578
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 5 criteria provided, multiple submitters, no conflicts Dec 15, 2020 RCV000013173.24
Pathogenic 2 criteria provided, multiple submitters, no conflicts Sep 13, 2018 RCV000131301.8
Pathogenic 6 criteria provided, multiple submitters, no conflicts Jan 4, 2021 RCV000213054.10
Pathogenic 2 criteria provided, multiple submitters, no conflicts Oct 21, 2020 RCV000204931.11
Pathogenic 1 criteria provided, single submitter Oct 31, 2018 RCV000763419.1
Pathogenic 1 criteria provided, single submitter - RCV001270268.1
Pathogenic 1 criteria provided, single submitter - RCV001270269.1
Pathogenic 1 no assertion criteria provided Jul 29, 2016 RCV000239398.1
Likely pathogenic 1 no assertion criteria provided Jul 14, 2015 RCV000421746.1
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 no assertion criteria provided Mar 19, 2021 RCV001527463.1
not provided 1 no assertion provided Mar 10, 2016 RCV000428918.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
TP53 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
2205 2268

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Apr 17, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
PreventionGenetics,PreventionGenetics
Accession: SCV000806241.1
Submitted: (Jan 29, 2018)
Evidence details
Pathogenic
(Jul 24, 2017)
criteria provided, single submitter
Method: clinical testing
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Allele origin: germline
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000731790.2
Submitted: (Mar 21, 2019)
Evidence details
Publications
PubMed (11)
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)
Pathogenic
(Sep 13, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000186273.7
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (13)
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)
Pathogenic
(Dec 15, 2020)
criteria provided, single submitter
Method: research
Li-Fraumeni syndrome 1
Allele origin: germline
Department of Pediatrics,Memorial Sloan Kettering Cancer Center
Accession: SCV001478188.1
Submitted: (Dec 16, 2020)
Evidence details
Publications
PubMed (1)
Pathogenic
(Jan 04, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000211798.12
Submitted: (Jul 20, 2021)
Evidence details
Comment:
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato et al., 2003; Monti et al., 2011; Wasserman et al., … (more)
Pathogenic
(Mar 18, 2016)
criteria provided, single submitter
Method: clinical testing
Li-Fraumeni syndrome 1
Allele origin: unknown
Counsyl
Accession: SCV000488375.1
Submitted: (Nov 23, 2016)
Evidence details
Publications
PubMed (11)
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
Bone osteosarcoma
Carcinoma of pancreas
Choroid plexus papilloma
Nasopharyngeal carcinoma
Basal cell carcinoma, susceptibility to, 7
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000894156.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Pathogenic
(Apr 15, 2015)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000905051.1
Submitted: (Nov 06, 2018)
Evidence details
Pathogenic
(-)
criteria provided, single submitter
Method: case-control
Squamous cell carcinoma of the head and neck
Allele origin: somatic
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo
Accession: SCV001450483.1
Submitted: (Dec 08, 2020)
Evidence details
Publications
PubMed (1)
Pathogenic
(-)
criteria provided, single submitter
Method: case-control
Colorectal cancer
Allele origin: somatic
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo
Accession: SCV001450484.1
Submitted: (Dec 08, 2020)
Evidence details
Publications
PubMed (2)
Pathogenic
(Oct 21, 2020)
criteria provided, single submitter
Method: clinical testing
Li-Fraumeni syndrome
Allele origin: germline
Invitae
Accession: SCV000261917.9
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (13)
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)
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001906154.1
Submitted: (Sep 20, 2021)
Evidence details
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Human Genetics - Radboudumc,Radboudumc
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959136.1
Submitted: (Sep 30, 2021)
Evidence details
Pathogenic
(Jul 24, 2014)
no assertion criteria provided
Method: clinical testing
Li-Fraumeni syndrome 1
Allele origin: germline
Pathway Genomics
Accession: SCV000189994.1
Submitted: (Aug 08, 2014)
Evidence details
Publications
PubMed (4)
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: unknown
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000692083.1
Submitted: (Oct 31, 2017)
Evidence details
Likely pathogenic
(Dec 01, 2018)
no assertion criteria provided
Method: research
Neoplasm of ovary
Allele origin: somatic
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne
Accession: SCV000923920.1
Submitted: (Feb 22, 2019)
Evidence details
Pathogenic
(Aug 01, 2005)
no assertion criteria provided
Method: literature only
LI-FRAUMENI SYNDROME 1
Allele origin: germline
OMIM
Accession: SCV000033420.4
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (2)
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
Li-Fraumeni syndrome 1
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: SCV001551443.1
Submitted: (Mar 31, 2021)
Evidence details
Comment:
The TP53 p.Arg175His variant was identified in 14 of 2378 proband chromosomes (frequency: 0.006) from individuals or families with Li Fraumeni syndrome, breast, ovarian and/or … (more)
Pathogenic
(Jul 29, 2016)
no assertion criteria provided
Method: clinical testing
Esophageal cancer
(Somatic mutation)
Allele origin: somatic
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo
Accession: SCV000297733.1
Submitted: (Aug 09, 2016)
Evidence details
Comment:
SIFT:Deleterious (score: 0) MutationTaster:Disease causing (p-value: 1)
Likely pathogenic
(Jul 14, 2015)
no assertion criteria provided
Method: literature only
Neoplasm
(Somatic mutation)
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000504891.1
Submitted: (Jul 18, 2016)
Evidence details
Publications
PubMed (3)
Other databases
http://docm.genome.wustl.edu/var…
Pathogenic
(Apr 30, 2019)
no assertion criteria provided
Method: research
Lip and oral cavity carcinoma
Allele origin: somatic
Institute of Medical Sciences, Banaras Hindu University
Accession: SCV001432233.1
Submitted: (Feb 01, 2020)
Evidence details
Publications
PubMed (1)
Pathogenic
(Mar 19, 2021)
no assertion criteria provided
Method: clinical testing
Familial cancer of breast
Allele origin: somatic
University Health Network,Princess Margaret Cancer Centre
Accession: SCV001738476.1
Submitted: (May 19, 2021)
Evidence details
Pathogenic
(-)
no assertion criteria provided
Method: clinical testing
not provided
Allele origin: germline
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808819.1
Submitted: (Aug 24, 2021)
Evidence details
not provided
(Mar 10, 2016)
no assertion provided
Method: literature only
Breast neoplasm
(Somatic mutation)
Allele origin: somatic
Database of Curated Mutations (DoCM)
Accession: SCV000504892.1
Submitted: (Jul 18, 2016)
Evidence details
Publications
PubMed (2)
Other databases
http://docm.genome.wustl.edu/var…

Functional evidence

Help
Functional consequence Method Result Submitter Supporting information
variation affecting protein function
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo
Accession: SCV000297733.1
Submitted: (Aug 09, 2016)
Evidence details

Citations for this variant

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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
Mutational spectrum of tobacco associated oral squamous carcinoma and its therapeutic significance. Batta N World journal of surgical oncology 2019 PMID: 31775759
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
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. Mandelker D JAMA 2017 PMID: 28873162
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
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 - - - -

Text-mined citations for rs28934578...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 02, 2021