VCV000012374.76 - ClinVar

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

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Li-Fraumeni syndrome

Classification is based on the expert panel submission

Sep 2024 by ClinGen TP53 Variant Curation Expert Panel, ClinGen

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

Oncogenicity

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Oncogenic

This classification is based on the single submission received

The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Variant Details

Identifiers

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

Variation ID: 12374 Accession: VCV000012374.76

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	Jun 29, 2025	Sep 6, 2024
Somatic - Oncogenicity	Aug 11, 2024	Mar 11, 2025	Mar 4, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_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_001126112.3:c.524G>A	NP_001119584.1:p.Arg175His	missense
NM_001126113.3:c.524G>A	NP_001119585.1:p.Arg175His	missense
NM_001126114.1:c.524G>A
NM_001126114.3:c.524G>A	NP_001119586.1:p.Arg175His	missense
NM_001126115.2:c.128G>A	NP_001119587.1:p.Arg43His	missense
NM_001126116.2:c.128G>A	NP_001119588.1:p.Arg43His	missense
NM_001126117.2:c.128G>A	NP_001119589.1:p.Arg43His	missense
NM_001126118.2:c.407G>A	NP_001119590.1:p.Arg136His	missense
NM_001276695.3:c.407G>A	NP_001263624.1:p.Arg136His	missense
NM_001276696.3:c.407G>A	NP_001263625.1:p.Arg136His	missense
NM_001276697.3:c.47G>A	NP_001263626.1:p.Arg16His	missense
NM_001276698.3:c.47G>A	NP_001263627.1:p.Arg16His	missense
NM_001276699.3:c.47G>A	NP_001263628.1:p.Arg16His	missense
NM_001276760.3:c.407G>A	NP_001263689.1:p.Arg136His	missense
NM_001276761.3: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
	P04637:p.Arg175His

... more HGVS ... less HGVS

Protein change

R175H, R136H, R43H, R16H

Other names

p.R175H:CGC>CAC
NM_000546.6(TP53):c.524G>A

Canonical SPDI

NC_000017.11:7675087:C:T

Functional consequence Help The 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) Help The 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

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA000251 UniProtKB: P04637#VAR_005932 OMIM: 191170.0030 dbSNP: rs28934578 VarSome

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
Gene	OMIM	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	3584	3685

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.
Li-Fraumeni syndrome 1	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Nov 12, 2024	RCV000013173.42
Hereditary cancer-predisposing syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 9, 2024	RCV000131301.25
Li-Fraumeni syndrome	Pathogenic (6)	reviewed by expert panel	Sep 6, 2024	RCV000204931.33
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Mar 4, 2025	RCV000213054.29
Malignant tumor of esophagus	Pathogenic (1)	no assertion criteria provided	Jul 29, 2016	RCV000239398.10
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jul 1, 2021	RCV003162247.8
Ovarian neoplasm	Likely pathogenic (1)	no assertion criteria provided	Dec 1, 2018	RCV000785352.10
Lip and oral cavity carcinoma	Pathogenic (1)	no assertion criteria provided	Apr 30, 2019	RCV001255668.9
Squamous cell carcinoma of the head and neck	Pathogenic (1)	criteria provided, single submitter	-	RCV001270268.10
Familial cancer of breast	Pathogenic (1)	no assertion criteria provided	Mar 19, 2021	RCV001527463.11
Colorectal cancer	Pathogenic (1)	criteria provided, single submitter	-	RCV001270269.10
TP53-related disorder	Pathogenic (1)	criteria provided, single submitter	May 1, 2024	RCV004797760.1
Adrenocortical carcinoma, hereditary Basal cell carcinoma, susceptibility to, 7 Bone marrow failure syndrome 5 Bone osteosarcoma Carcinoma of pancreas Choroid plexus papilloma Colorectal cancer Familial cancer of breast Glioma susceptibility 1 Hepatocellular carcinoma Li-Fraumeni syndrome 1 Nasopharyngeal carcinoma	Pathogenic (1)	criteria provided, single submitter	Apr 10, 2022	RCV002476956.8
Adrenocortical carcinoma, hereditary	Pathogenic (1)	criteria provided, single submitter	Mar 28, 2024	RCV003466854.2
click to load more conditions 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 (Sep 06, 2024) C Contributing to aggregate classification	reviewed by expert panel (ClinGen TP53 ACMG Specifications TP53 V2.0.0) 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: SCV005201131.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7447e408-66fd-43ee-8fc8-6012f43d7ada Comment: The NM_000546.6: c.524G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 175 (p.Arg175His). This variant … (more) The NM_000546.6: c.524G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 175 (p.Arg175His). This variant has been reported in 3 unrelated families meeting Classic and Revised Chompret criteria.Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate: 8825920, 11370630, 8164043). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in 1 family (PP1_Moderate; PMID: 8825920). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Computational predictor scores (BayesDel = 0.54619; Align GVGD = Class C25) 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). This variant has an allele frequency of 0.000005932 (7/1180032 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as [CLASSIFICATION] for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP1_Moderate, PM1, PS4_Moderate, PP3, PM2_Supporting. (Bayesian Points: 12; VCEP specifications version 2.0; 9/6/2024) (less)

Pathogenic (Apr 17, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000806241.1 First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018

Pathogenic (Jul 24, 2017) N Not contributing to aggregate classification	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Li-Fraumeni syndrome (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000731790.2 First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019	Publications: PubMed (11) PubMed: 8164043‚ 23792586‚ 19881536‚ 20689556‚ 9047394‚ 16401470‚ 18511570‚ 22006311‚ 27374712‚ 21761402‚ 28349240 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 (Apr 10, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV000894156.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30

Pathogenic (Nov 03, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002011128.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023

Pathogenic (May 11, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004044216.2 First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023	Publications: PubMed (6) PubMed: 8825920‚ 8118819‚ 7887414‚ 14743206‚ 15607980‚ 8023157 Comment: This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:8825920, 8118819, 7887414]. Functional studies indicate … (more) This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:8825920, 8118819, 7887414]. Functional studies indicate this variant impacts protein function [PMID: 14743206, 15607980]. This variant is expected to disrupt protein structure [PMID: 8023157, Myriad internal data]. (less)

Pathogenic (Sep 18, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004823789.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (10) PubMed: 8164043‚ 8825920‚ 12826609‚ 15607980‚ 15607981‚ 23263379‚ 23792586‚ 25059482‚ 29979965‚ 30224644 Comment: This missense variant replaces arginine with histidine at codon 175 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant … (more) This missense variant replaces arginine with histidine at codon 175 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of TP53 protein function (PMID: 12826609, 15607981, 23263379, 29979965, 30224644), causes chromosomal instability (PMID: 25059482), and promotes tumor cell invasion (PMID: 15607981, 23792586). In mouse models of Li-Fraumeni syndrome, this variant has also been shown to impair TP53 function and cause TP53-related tumors (PMID: 15607980, 15607981). This variant has been reported in individuals affected with Li-Fraumeni syndrome meeting classic or Chompret diagnostic criteria (PMID: 8164043 , 8825920, 16401470, 21761402, 23172776, 27374712, 27516001). This variant has been shown to segregate with disease in a 4-generation extended family affected with Li-Fraumeni syndrome (PMID: 8825920). This variant has been identified in 1/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less) Number of individuals with the variant: 1 Zygosity: Single Heterozygote

Pathogenic (Jan 07, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002074556.3 First in ClinVar: Feb 12, 2022 Last updated: May 12, 2024	Comment: Variant summary: TP53 c.524G>A (p.Arg175His) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four … (more) Variant summary: TP53 c.524G>A (p.Arg175His) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251276 control chromosomes. c.524G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome, including 2 families where the variant strongly segregated with disease (Varley_1995, Varley_1997, etc). These data indicate that the variant is very likely to be associated with disease. In vitro functional studies show that R175H results in decreased activation of Tp53 targets, and additionally confers a gain of function to Tp53, resulting in aberrant activation of gene transcription and enhanced cell migration (TP53 database, Yeudall_2012). Additional evidence from an animal model indicates that this variant contributes to a phenotype similar to tumorigenesis (including thymic tumors, sarcomas, peripheral lymphomas and germ-cell tumors) (Liu_2010). Ten ClinVar submitters have assessed this variant since 2014: all ten classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)

Pathogenic (May 01, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	TP53-related disorder Affected status: yes Allele origin: somatic	Swedish National ChiCaP Initative, Genomic Medicine Sweden Accession: SCV005419199.1 First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024

Pathogenic (Jan 10, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome Affected status: yes Allele origin: germline	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Accession: SCV005685067.1 First in ClinVar: Feb 01, 2025 Last updated: Feb 01, 2025	Publications: PubMed (1) PubMed: 29324801 Comment: The following ACMG criteria was used: PS3, PP1_MOD, PM1, PS4_MOD, PP3, PM2_SUP

Pathogenic (Dec 15, 2020) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: germline	Department of Pediatrics, Memorial Sloan Kettering Cancer Center Accession: SCV001478188.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Publications: PubMed (1) PubMed: 28873162

Pathogenic (Jan 04, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000211798.12 First in ClinVar: Feb 24, 2015 Last updated: Jul 24, 2021	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) 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., 2015; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31447099, 31105275, 15510160, 12826609, 19556618, 21343334, 25584008, 29979965, 8118819, 8164043, 10864200, 12200603, 16401470, 22233476, 28369373, 30577483, 30840781, 30093976, 29324801, 30092803, 30720243, 30709875, 28472496, 29753700, 29360550, 28975465, 29470806, 19127115, 29360161, 28818432, 29416795, 27153395, 12610779, 11494139, 11370630, 8308926, 7887414, 8099841, 23792586, 20689556, 15492269, 21426305, 22006311, 24573247, 22286061, 21305319, 17606709, 21761402, 24651015, 20128691, 24729566, 15170137, 29489754, 28861920, 28724667, 15607981, 15607980, 27516001, 27374712, 27714481, 27501770, 27323394, 23172776, 22265402, 21601526, 22851211, 21059199, 20501846, 18511570, 17308077, 16551709, 15951970) (less)

Pathogenic (Jun 18, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002582493.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022

Pathogenic (Jun 18, 2022) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002583153.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022

Pathogenic (Mar 28, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adrenocortical carcinoma, hereditary Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004206223.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024

Pathogenic (Sep 19, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000186273.10 First in ClinVar: Aug 06, 2014 Last updated: Jan 13, 2025	Publications: PubMed (13) PubMed: 12826609‚ 16401470‚ 19127115‚ 21343334‚ 21761402‚ 22233476‚ 23263379‚ 23792586‚ 27153395‚ 27374712‚ 27516001‚ 8164043‚ 8825920 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 mutation occurs at a well-characterized mutation hotspot (codon 175) in the 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). This variant is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)

Pathogenic (Dec 09, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV005688871.1 First in ClinVar: Feb 08, 2025 Last updated: Feb 08, 2025	Comment: The missense variant NM_000546.6(TP53):c.524G>A (p.Arg175His) causes the same amino acid change as a previously established pathogenic variant. There is a small physicochemical difference between arginine … (more) The missense variant NM_000546.6(TP53):c.524G>A (p.Arg175His) causes the same amino acid change as a previously established pathogenic variant. There is a small physicochemical difference between arginine and histidine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene TP53 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.15. The p.Arg175His missense variant is predicted to be damaging by both SIFT and PolyPhen2. . The nucleotide c.524 in TP53 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic (less)

Pathogenic (Jan 25, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000261917.13 First in ClinVar: Jan 31, 2016 Last updated: Feb 25, 2025	Publications: PubMed (15) PubMed: 28492532‚ 8164043‚ 8825920‚ 16401470‚ 21761402‚ 22006311‚ 12826609‚ 29979965‚ 30224644‚ 12007217‚ 15607980‚ 15607981‚ 20516128‚ 23263379‚ 24573247 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 175 of the TP53 protein (p.Arg175His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 175 of the TP53 protein (p.Arg175His). This variant is present in population databases (rs28934578, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 8164043, 8825920, 16401470, 21761402, 22006311). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12374). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12007217, 12826609, 15607980, 15607981, 20516128, 23263379, 24573247, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. (less)

Pathogenic (Mar 04, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV005872480.1 First in ClinVar: Mar 11, 2025 Last updated: Mar 11, 2025	Publications: PubMed (7) PubMed: 27516001‚ 19127115‚ 21305319‚ 27374712‚ 23172776‚ 12826609‚ 30224644

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV001450483.2 First in ClinVar: Dec 12, 2020 Last updated: Apr 13, 2025	Publications: PubMed (1) PubMed: 30816478 Age: 50-59 years Sex: male Geographic origin: Sri Lanka

Pathogenic (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: case-control	Colorectal cancer Affected status: yes Allele origin: somatic	Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo Accession: SCV001450484.2 First in ClinVar: Dec 12, 2020 Last updated: Apr 13, 2025	Publications: PubMed (2) PubMed: 30816478‚ 32000721 Age: 60-69 years Sex: male Geographic origin: Sri Lanka

Pathogenic (Nov 12, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: maternal	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV005368520.3 First in ClinVar: Oct 13, 2024 Last updated: Apr 13, 2025	Comment: Criteria applied: PS3,PS4,PM1,PP3 Clinical Features: Family history of cancer (present) Sex: female

Pathogenic (Aug 05, 2024) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000905051.4 First in ClinVar: May 19, 2019 Last updated: May 03, 2025	Publications: PubMed (15) PubMed: 8164043‚ 8825920‚ 12826609‚ 15607980‚ 15607981‚ 16401470‚ 21761402‚ 23172776‚ 23263379‚ 23792586‚ 25059482‚ 27374712‚ 27516001‚ 29979965‚ 30224644 Comment: This missense variant replaces arginine with histidine at codon 175 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant … (more) This missense variant replaces arginine with histidine at codon 175 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant results in the loss of TP53 protein function (PMID: 12826609, 15607981, 23263379, 29979965, 30224644), causes chromosomal instability (PMID: 25059482), and promotes tumor cell invasion (PMID: 15607981, 23792586). In mouse models of Li-Fraumeni syndrome, this variant has also been shown to impair TP53 function and cause TP53-related tumors (PMID: 15607980, 15607981). This variant has been reported in individuals affected with Li-Fraumeni syndrome meeting classic or Chompret diagnostic criteria (PMID: 8164043 , 8825920, 16401470, 21761402, 23172776, 27374712, 27516001). This variant has been shown to segregate with disease in a 4-generation extended family affected with Li-Fraumeni syndrome (PMID: 8825920). This variant has been identified in 1/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less) Platform type: NGS

Pathogenic (Jul 24, 2014) N Not contributing to aggregate classification	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	Publications: PubMed (4) PubMed: 17606709‚ 18511570‚ 9047394‚ 23161690

Likely pathogenic (Dec 01, 2018) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Ovarian neoplasm Affected status: yes Allele origin: somatic	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne Accession: SCV000923920.1 First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019	Platform type: next-gen sequencing

Pathogenic (Apr 30, 2019) N Not contributing to aggregate classification	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	Publications: PubMed (1) PubMed: 31775759

Pathogenic (Mar 19, 2021) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Familial cancer of breast Affected status: no Allele origin: somatic	University Health Network, Princess Margaret Cancer Centre Accession: SCV001738476.1 First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021	Secondary finding: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808819.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959136.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021

Pathogenic (Jul 01, 2021) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Gastric cancer Affected status: unknown Allele origin: germline	Laboratory for Genotyping Development, RIKEN Accession: SCV002758490.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 36988593

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000692083.1 First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018

Pathogenic (Aug 01, 2005) N Not contributing to aggregate classification	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	Publications: PubMed (2) PubMed: 12619118‚ 15977174 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 (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	None 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: SCV001551443.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	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) 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 colon cancer (Walsh 2011, Melhem-Bertrandt 2012, Wong 2006, Bougeard 2008, Damineni 2014). This variant has also been identified in a child diagnosed with adrenocortical carcinoma at 6 months of age (Choong 2012) and a family that includes two individuals diagnosed with childhood sarcomas and four individuals diagnosed with brain tumours (Varley 1995). The variant was identified in dbSNP and ClinVar (classified as pathogenic by GeneDx, Invitae, Ambry Genetics, and 8 other submitters) . The variant was identified in control databases in 1 of 251276 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 1 of 113600 chromosomes (freq: 0.000009), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The R175 residue is a mutation hotspot and results in a structurally unstable, unfolded p53 protein (Xu 2014). The R175H variant has been shown to confer oncogenic gain of function to the p53 protein by multiple studies (Petitjean 2007, Capponcelli 2005), which is hypothesized to occur via the increased activation of the c-Met receptor tyrosine kinase and/or the inactivation of the ATM-dependent DNA damage response, resulting in a defective G2/M checkpoint (Grugan 2013, Liu 2010). The p.Arg175 residue is conserved across mammals and other organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the His 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less)

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes 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 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021

Pathogenic (Jul 29, 2016) N Not contributing to aggregate classification	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: SCV000297733.2 First in ClinVar: Aug 13, 2016 Last updated: Apr 13, 2025	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 Platform type: Sanger sequencing

Pathogenic (Mar 18, 2016) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000488375.3 First in ClinVar: Sep 04, 2016 Last updated: Jun 29, 2025	Publications: PubMed (11) PubMed: 21761402‚ 22233476‚ 19881536‚ 21305319‚ 24573247‚ 16401470‚ 21343334‚ 17606709‚ 20128691‚ 20689556‚ 23792586 Comment: This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

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Comment:

The NM_000546.6: c.524G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 175 (p.Arg175His). This variant has been reported in 3 unrelated families meeting Classic and Revised Chompret criteria.Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate: 8825920, 11370630, 8164043). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in 1 family (PP1_Moderate; PMID: 8825920). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Computational predictor scores (BayesDel = 0.54619; Align GVGD = Class C25) 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). This variant has an allele frequency of 0.000005932 (7/1180032 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as [CLASSIFICATION] for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP1_Moderate, PM1, PS4_Moderate, PP3, PM2_Supporting. (Bayesian Points: 12; VCEP specifications version 2.0; 9/6/2024)

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 variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:8825920, 8118819, 7887414]. Functional studies indicate this variant impacts protein function [PMID: 14743206, 15607980]. This variant is expected to disrupt protein structure [PMID: 8023157, Myriad internal data].

Comment:

This missense variant replaces arginine with histidine at codon 175 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in the loss of TP53 protein function (PMID: 12826609, 15607981, 23263379, 29979965, 30224644), causes chromosomal instability (PMID: 25059482), and promotes tumor cell invasion (PMID: 15607981, 23792586). In mouse models of Li-Fraumeni syndrome, this variant has also been shown to impair TP53 function and cause TP53-related tumors (PMID: 15607980, 15607981). This variant has been reported in individuals affected with Li-Fraumeni syndrome meeting classic or Chompret diagnostic criteria (PMID: 8164043 , 8825920, 16401470, 21761402, 23172776, 27374712, 27516001). This variant has been shown to segregate with disease in a 4-generation extended family affected with Li-Fraumeni syndrome (PMID: 8825920). This variant has been identified in 1/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

Variant summary: TP53 c.524G>A (p.Arg175His) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251276 control chromosomes. c.524G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome, including 2 families where the variant strongly segregated with disease (Varley_1995, Varley_1997, etc). These data indicate that the variant is very likely to be associated with disease. In vitro functional studies show that R175H results in decreased activation of Tp53 targets, and additionally confers a gain of function to Tp53, resulting in aberrant activation of gene transcription and enhanced cell migration (TP53 database, Yeudall_2012). Additional evidence from an animal model indicates that this variant contributes to a phenotype similar to tumorigenesis (including thymic tumors, sarcomas, peripheral lymphomas and germ-cell tumors) (Liu_2010). Ten ClinVar submitters have assessed this variant since 2014: all ten classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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., 2015; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31447099, 31105275, 15510160, 12826609, 19556618, 21343334, 25584008, 29979965, 8118819, 8164043, 10864200, 12200603, 16401470, 22233476, 28369373, 30577483, 30840781, 30093976, 29324801, 30092803, 30720243, 30709875, 28472496, 29753700, 29360550, 28975465, 29470806, 19127115, 29360161, 28818432, 29416795, 27153395, 12610779, 11494139, 11370630, 8308926, 7887414, 8099841, 23792586, 20689556, 15492269, 21426305, 22006311, 24573247, 22286061, 21305319, 17606709, 21761402, 24651015, 20128691, 24729566, 15170137, 29489754, 28861920, 28724667, 15607981, 15607980, 27516001, 27374712, 27714481, 27501770, 27323394, 23172776, 22265402, 21601526, 22851211, 21059199, 20501846, 18511570, 17308077, 16551709, 15951970)

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 mutation occurs at a well-characterized mutation hotspot (codon 175) in the 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). This variant is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

The missense variant NM_000546.6(TP53):c.524G>A (p.Arg175His) causes the same amino acid change as a previously established pathogenic variant. There is a small physicochemical difference between arginine and histidine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene TP53 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.15. The p.Arg175His missense variant is predicted to be damaging by both SIFT and PolyPhen2. . The nucleotide c.524 in TP53 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 175 of the TP53 protein (p.Arg175His). This variant is present in population databases (rs28934578, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 8164043, 8825920, 16401470, 21761402, 22006311). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12374). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12007217, 12826609, 15607980, 15607981, 20516128, 23263379, 24573247, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.

Comment:

This missense variant replaces arginine with histidine at codon 175 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant results in the loss of TP53 protein function (PMID: 12826609, 15607981, 23263379, 29979965, 30224644), causes chromosomal instability (PMID: 25059482), and promotes tumor cell invasion (PMID: 15607981, 23792586). In mouse models of Li-Fraumeni syndrome, this variant has also been shown to impair TP53 function and cause TP53-related tumors (PMID: 15607980, 15607981). This variant has been reported in individuals affected with Li-Fraumeni syndrome meeting classic or Chompret diagnostic criteria (PMID: 8164043 , 8825920, 16401470, 21761402, 23172776, 27374712, 27516001). This variant has been shown to segregate with disease in a 4-generation extended family affected with Li-Fraumeni syndrome (PMID: 8825920). This variant has been identified in 1/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

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 colon cancer (Walsh 2011, Melhem-Bertrandt 2012, Wong 2006, Bougeard 2008, Damineni 2014). This variant has also been identified in a child diagnosed with adrenocortical carcinoma at 6 months of age (Choong 2012) and a family that includes two individuals diagnosed with childhood sarcomas and four individuals diagnosed with brain tumours (Varley 1995). The variant was identified in dbSNP and ClinVar (classified as pathogenic by GeneDx, Invitae, Ambry Genetics, and 8 other submitters) . The variant was identified in control databases in 1 of 251276 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 1 of 113600 chromosomes (freq: 0.000009), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The R175 residue is a mutation hotspot and results in a structurally unstable, unfolded p53 protein (Xu 2014). The R175H variant has been shown to confer oncogenic gain of function to the p53 protein by multiple studies (Petitjean 2007, Capponcelli 2005), which is hypothesized to occur via the increased activation of the c-Met receptor tyrosine kinase and/or the inactivation of the ATM-dependent DNA damage response, resulting in a defective G2/M checkpoint (Grugan 2013, Liu 2010). The p.Arg175 residue is conserved across mammals and other organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the His 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help 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 Help A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
variation affecting protein function (VariO:0003)			Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo Accession: SCV000297733.2

Comment:

This missense variant replaces arginine with histidine at codon 175 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant results in the loss of TP53 protein function (PMID: 12826609, 15607981, 23263379, 29979965, 30224644), causes chromosomal instability (PMID: 25059482), and promotes tumor cell invasion (PMID: 15607981, 23792586). In mouse models of Li-Fraumeni syndrome, this variant has also been shown to impair TP53 function and cause TP53-related tumors (PMID: 15607980, 15607981). This variant has been reported in individuals affected with Li-Fraumeni syndrome meeting classic or Chompret diagnostic criteria (PMID: 8164043 , 8825920, 16401470, 21761402, 23172776, 27374712, 27516001). This variant has been shown to segregate with disease in a 4-generation extended family affected with Li-Fraumeni syndrome (PMID: 8825920). This variant has been identified in 1/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer.	Usui Y	The New England journal of medicine	2023	PMID: 36988593
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
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
Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark.	Stoltze U	PloS one	2018	PMID: 29324801
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
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
Different TP53 mutations are associated with specific chromosomal rearrangements, telomere length changes, and remodeling of the nuclear architecture of telomeres.	Samassekou O	Genes, chromosomes & cancer	2014	PMID: 25059482
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
Drastic effect of germline TP53 missense mutations in Li-Fraumeni patients.	Zerdoumi Y	Human mutation	2013	PMID: 23172776
The TP53 website: an integrative resource centre for the TP53 mutation database and TP53 mutant analysis.	Leroy B	Nucleic acids research	2013	PMID: 23161690
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
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
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
Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes.	Willis A	Oncogene	2004	PMID: 14743206
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
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
Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome.	Frebourg T	American journal of human genetics	1995	PMID: 7887414
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
Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families.	Birch JM	Cancer research	1994	PMID: 8118819
Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations.	Cho Y	Science (New York, N.Y.)	1994	PMID: 8023157
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7447e408-66fd-43ee-8fc8-6012f43d7ada	-	-	-	-
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Conditions - Somatic

Tumor type Help The tumor type for this variant-condition (RCV) record in ClinVar.	Clinical impact (# of submissions) Help The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Oncogenicity Help The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the tumor type.	Variation/condition record Help The most recent date that a submitter evaluated this variant for the tumor type.
Neoplasm		Oncogenic criteria provided, single submitter	Mar 4, 2025	RCV000421746.12

Submissions - Somatic

Oncogenicity Help The submitted oncogenicity 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)	Tumor type Help The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.

Oncogenic (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ClinGen/CGC/VICC Guidelines for Oncogenicity, 2022) Method: clinical testing	Neoplasm Affected status: unknown Allele origin: somatic	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV005094440.2 First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025	Publications: PubMed (11) PubMed: 22713868‚ 10713666‚ 21445056‚ 15781620‚ 14743206‚ 19881536‚ 22114072‚ 25584008‚ 31068365‚ 31395785‚ 37030635

Comment:

This missense variant replaces arginine with histidine at codon 175 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant results in the loss of TP53 protein function (PMID: 12826609, 15607981, 23263379, 29979965, 30224644), causes chromosomal instability (PMID: 25059482), and promotes tumor cell invasion (PMID: 15607981, 23792586). In mouse models of Li-Fraumeni syndrome, this variant has also been shown to impair TP53 function and cause TP53-related tumors (PMID: 15607980, 15607981). This variant has been reported in individuals affected with Li-Fraumeni syndrome meeting classic or Chompret diagnostic criteria (PMID: 8164043 , 8825920, 16401470, 21761402, 23172776, 27374712, 27516001). This variant has been shown to segregate with disease in a 4-generation extended family affected with Li-Fraumeni syndrome (PMID: 8825920). This variant has been identified in 1/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Citations for somatic classification of this variant

Title	Author	Journal	Year	Link
Mutant p53 activates hnRNPA2B1-AGAP1-mediated exosome formation to promote esophageal squamous cell carcinoma progression.	Feng R	Cancer letters	2023	PMID: 37030635
A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies.	Boettcher S	Science (New York, N.Y.)	2019	PMID: 31395785
A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1.	Loizou E	Cancer discovery	2019	PMID: 31068365
Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study.	Wasserman JD	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2015	PMID: 25584008
Mutant p53: one name, many proteins.	Freed-Pastor WA	Genes & development	2012	PMID: 22713868
Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration.	Yeudall WA	Carcinogenesis	2012	PMID: 22114072
Gain of function of mutant p53 by coaggregation with multiple tumor suppressors.	Xu J	Nature chemical biology	2011	PMID: 21445056
A common gain of function of p53 cancer mutants in inducing genetic instability.	Liu DP	Oncogene	2010	PMID: 19881536
Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s.	Kakudo Y	Cancer research	2005	PMID: 15781620
Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes.	Willis A	Oncogene	2004	PMID: 14743206
Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy.	Bullock AN	Oncogene	2000	PMID: 10713666
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Text-mined citations for rs28934578 ...

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 Jun 29, 2025

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Conditions - Somatic

Submissions - Somatic

Citations for somatic classification of this variant

Text-mined citations for rs28934578 ...