The p.R110C variant (also known as c.328C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 328. The arginine at codon 110 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in both cases and controls in breast cancer case control studies, and has also been reported in a high-risk breast cancer proband from Sweden (Momozowa Y et al. Nat Commun 2018 10;9(1):4083; Dorling et al. N Engl J Med 2021 02;384:428-439; Kharaziha P et al. Clin Genet 2019 09;96(3):216-225). This variant is in the DNA binding domain of the TP53 protein and is reported to have reduced transactivation capacity compared to wild type (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387; Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8). Two other alterations at this amino acid position, p.R110L and p.R110P, have been detected in individuals with a diagnosis of Li-Fraumeni syndrome (LFS) based on personal and family history (Rines RD et al. Carcinogenesis. 1998 Jun;19(6):979-84; Masciari S et al. Genet Med. 2011 Jul;13(7):651-7). This alteration has been observed in individuals with TP53 related tumors, but not classic Li-Fraumeni syndrome (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.328C>T (p.Arg110Cys)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Uncertain significance
11 out of 14 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
14
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
Likely oncogenic
This classification is based on the single submission received
Help
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.
1
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.328C>T (p.Arg110Cys)
Variation ID: 142206 Accession: VCV000142206.57
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.1 17: 7676041 (GRCh38) [ NCBI UCSC ] 17: 7579359 (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 Jan 9, 2017 May 3, 2025 Mar 11, 2025 Somatic - Oncogenicity Aug 11, 2024 Mar 11, 2025 Mar 4, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.328C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg110Cys missense NM_001126112.3:c.328C>T NP_001119584.1:p.Arg110Cys missense NM_001126113.3:c.328C>T NP_001119585.1:p.Arg110Cys missense NM_001126114.3:c.328C>T NP_001119586.1:p.Arg110Cys missense NM_001126118.2:c.211C>T NP_001119590.1:p.Arg71Cys missense NM_001276695.3:c.211C>T NP_001263624.1:p.Arg71Cys missense NM_001276696.3:c.211C>T NP_001263625.1:p.Arg71Cys missense NM_001276760.3:c.211C>T NP_001263689.1:p.Arg71Cys missense NM_001276761.3:c.211C>T NP_001263690.1:p.Arg71Cys missense NC_000017.11:g.7676041G>A NC_000017.10:g.7579359G>A NG_017013.2:g.16510C>T LRG_321:g.16510C>T LRG_321t1:c.328C>T LRG_321p1:p.Arg110Cys P04637:p.Arg110Cys - Protein change
- R110C, R71C
- Other names
- -
- Canonical SPDI
- NC_000017.11:7676040:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
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. |
|---|---|---|---|---|
| Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 11, 2025 | RCV000131196.20 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 9, 2024 | RCV000195648.15 | |
| Uncertain significance (1) |
no assertion criteria provided
|
- | RCV001356391.5 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 4, 2025 | RCV002267879.10 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Dec 13, 2021 | RCV003149906.4 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 30, 2024 | RCV001704056.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jun 18, 2022 | RCV002288646.3 | |
|
TP53-related disorder
|
Uncertain significance (1) |
no assertion criteria provided
|
Oct 1, 2024 | RCV004797599.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Sep 09, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186146.11
First in ClinVar: Aug 06, 2014 Last updated: Jan 13, 2025 |
Comment:
The p.R110C variant (also known as c.328C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide … (more)
The p.R110C variant (also known as c.328C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 328. The arginine at codon 110 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in both cases and controls in breast cancer case control studies, and has also been reported in a high-risk breast cancer proband from Sweden (Momozowa Y et al. Nat Commun 2018 10;9(1):4083; Dorling et al. N Engl J Med 2021 02;384:428-439; Kharaziha P et al. Clin Genet 2019 09;96(3):216-225). This variant is in the DNA binding domain of the TP53 protein and is reported to have reduced transactivation capacity compared to wild type (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387; Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8). Two other alterations at this amino acid position, p.R110L and p.R110P, have been detected in individuals with a diagnosis of Li-Fraumeni syndrome (LFS) based on personal and family history (Rines RD et al. Carcinogenesis. 1998 Jun;19(6):979-84; Masciari S et al. Genet Med. 2011 Jul;13(7):651-7). This alteration has been observed in individuals with TP53 related tumors, but not classic Li-Fraumeni syndrome (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Dec 09, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254629.10
First in ClinVar: Oct 11, 2015 Last updated: Feb 16, 2025 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 110 of the TP53 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 110 of the TP53 protein (p.Arg110Cys). This variant is present in population databases (rs587781371, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 31081129, 32885271; internal data). ClinVar contains an entry for this variant (Variation ID: 142206). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 9290701, 12826609, 29979965, 30224644, 31081129). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(Sep 30, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000491052.3
First in ClinVar: Jan 09, 2017 Last updated: Oct 08, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22915647, 1655254, 26001148, 22610119, 25148578, 27721458, … (more)
Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22915647, 1655254, 26001148, 22610119, 25148578, 27721458, 15781620, 9290701, 34605602, 26687995, 8690195, 24797764, 25742471, 21118481, 25343854, 17982662, 31081129, 24076587, 23897043, 23894400, 21552135, 21445056, 16778209, 12826609, 11782540, 25952993, 23246812, 22186996, 21519010, 21343334, 20407015, 17606709, 27276561, 29979965, 37352403, 30224644, 36353970, 32885271, 15510160, 30327374, 30613367, 27463065, 27895058, 27959731, 27680515, 26230955) (less)
|
|
|
Uncertain significance
(Mar 11, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000686732.5
First in ClinVar: Feb 19, 2018 Last updated: May 03, 2025 |
Comment:
This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 9290701, 12826609, 15781620, 31081129), functional in human cell growth assays (PMID: 29979965, 30224644), and show cytoplasmic and perinuclear localization unlike wild-type protein (PMID: 31081129). This variant has been detected in an individual affected with choroid plexus carcinoma meeting Chompret criteria for Li-Fraumeni syndrome (PMCID: PMC9164685) and in at least six individuals affected with breast cancer (PMID: 31081129, 33471991). This variant has been identified in 5/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.329G>C (p.Arg110Pro) and c.329G>T (p.Arg110Leu), are considered to be disease-causing (ClinVar Variation ID: 233627, 406597), suggesting that arginine at this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Platform type: NGS
|
|
|
Uncertain significance
(Mar 04, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002551091.5
First in ClinVar: Jul 28, 2022 Last updated: Mar 11, 2025 |
|
|
|
Uncertain significance
(Jun 18, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002582676.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
|
Uncertain significance
(Jun 18, 2022)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002582115.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
|
|
Uncertain significance
(Dec 13, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV003838581.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
|
|
Uncertain significance
(Sep 29, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004100274.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Variant summary: TP53 c.328C>T (p.Arg110Cys) results in a non-conservative amino acid change located in the DNA-binding domain of the encoded protein sequence. Three of five … (more)
Variant summary: TP53 c.328C>T (p.Arg110Cys) results in a non-conservative amino acid change located in the DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes. c.328C>T has been reported in the literature in individuals affected with various cancers without evidence of causality (e.g. Kharaziha_2019, Kobayashi_2018, LernerEllis_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (e.g. Kharaziha_2019). The following publications have been ascertained in the context of this evaluation (PMID: 9290701, 31081129, 30613367, 32885271). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=7) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
|
|
|
Uncertain Significance
(Aug 28, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
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: SCV004823815.1
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)
|
Comment:
This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 9290701, 12826609, 15781620, 31081129), functional in human cell growth assays (PMID: 29979965, 30224644), and show cytoplasmic and perinuclear localization unlike wild-type protein (PMID: 31081129). This variant has been detected in an individual affected with choroid plexus carcinoma meeting Chompret criteria for Li-Fraumeni syndrome (PMCID: PMC9164685) and in at least six individuals affected with breast cancer (PMID: 31081129, 33471991). This variant has been identified in 5/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.329G>C (p.Arg110Pro) and c.329G>T (p.Arg110Leu), are considered to be disease-causing (ClinVar Variation ID: 233627, 406597), suggesting that arginine at this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
Zygosity: Single Heterozygote
|
|
|
Uncertain significance
(Aug 13, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV005625955.1
First in ClinVar: Jan 19, 2025 Last updated: Jan 19, 2025 |
Comment:
The TP53 c.328C>T (p.Arg110Cys) variant has been reported in the published literature in individuals with Li-Fraumeni syndrome (PMIDs: 31081129 (2019), 32885271 (2021), and 33471991 (2021)). … (more)
The TP53 c.328C>T (p.Arg110Cys) variant has been reported in the published literature in individuals with Li-Fraumeni syndrome (PMIDs: 31081129 (2019), 32885271 (2021), and 33471991 (2021)). Functional studies demonstrated that the effect on protein function was inconclusive (PMIDs: 9290701 (1997), 12826609 (2003), 29979965 (2018) and 31081129 (2019)). The frequency of this variant in the general population, 0.00023 (5/21646 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551544.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TP53 p.Arg110Cys variant was identified in the literature and has been previously reported as a somatic variant but not reported as a germline variant … (more)
The TP53 p.Arg110Cys variant was identified in the literature and has been previously reported as a somatic variant but not reported as a germline variant (see examples: Holstege 2009, Pain 2017, Holstege 2010). The variant was also identified in dbSNP (ID: rs587781371) as “With Uncertain significance allele”, in ClinVar (classified as a variant of uncertain significance 4x by Ambry Genetics, Color Genomics, Invitae, and GeneDx), Cosmic (17x somatic entries), and IARC TP53 Database (13 somatic mutations). The variant was not identified in COGR, LOVD 3.0, or the Database of germline p53 mutations. The variant was identified in control databases in 5 of 246096 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the Finnish population in 5 of 22298 chromosomes (freq: 0.000224), but not in the African, Ashkenazi Jewish, East Asian, European (Non-Finnish), Latino, or South Asian populations. The p.Arg110 residue has been classified as a somatic mutational hotspot (Walker et al 1999). Variants at the same amino acid residue have been previously seen and are classified on ClinVar: p.Arg110Pro is classified as likely pathogenic; p.Arg110Leu is classified as likely pathogenic and as a variant of uncertain significance; and p.Arg110Ser and p.Arg110His are both classified as variants of uncertain significance. The p.Arg110 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
|
|
|
Likely pathogenic
(Aug 26, 2022)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
BRCAlab, Lund University
Accession: SCV002589019.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
|
|
|
Uncertain significance
(Oct 01, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
TP53-related disorder
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV005419172.1
First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024 |
|
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| click to load more submissions click to collapse | |||||
Comment:
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 110 of the TP53 protein (p.Arg110Cys). This variant is present in population databases (rs587781371, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 31081129, 32885271; internal data). ClinVar contains an entry for this variant (Variation ID: 142206). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 9290701, 12826609, 29979965, 30224644, 31081129). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22915647, 1655254, 26001148, 22610119, 25148578, 27721458, 15781620, 9290701, 34605602, 26687995, 8690195, 24797764, 25742471, 21118481, 25343854, 17982662, 31081129, 24076587, 23897043, 23894400, 21552135, 21445056, 16778209, 12826609, 11782540, 25952993, 23246812, 22186996, 21519010, 21343334, 20407015, 17606709, 27276561, 29979965, 37352403, 30224644, 36353970, 32885271, 15510160, 30327374, 30613367, 27463065, 27895058, 27959731, 27680515, 26230955)
Comment:
This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 9290701, 12826609, 15781620, 31081129), functional in human cell growth assays (PMID: 29979965, 30224644), and show cytoplasmic and perinuclear localization unlike wild-type protein (PMID: 31081129). This variant has been detected in an individual affected with choroid plexus carcinoma meeting Chompret criteria for Li-Fraumeni syndrome (PMCID: PMC9164685) and in at least six individuals affected with breast cancer (PMID: 31081129, 33471991). This variant has been identified in 5/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.329G>C (p.Arg110Pro) and c.329G>T (p.Arg110Leu), are considered to be disease-causing (ClinVar Variation ID: 233627, 406597), suggesting that arginine at this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Variant summary: TP53 c.328C>T (p.Arg110Cys) results in a non-conservative amino acid change located in the DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes. c.328C>T has been reported in the literature in individuals affected with various cancers without evidence of causality (e.g. Kharaziha_2019, Kobayashi_2018, LernerEllis_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (e.g. Kharaziha_2019). The following publications have been ascertained in the context of this evaluation (PMID: 9290701, 31081129, 30613367, 32885271). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=7) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Comment:
This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 9290701, 12826609, 15781620, 31081129), functional in human cell growth assays (PMID: 29979965, 30224644), and show cytoplasmic and perinuclear localization unlike wild-type protein (PMID: 31081129). This variant has been detected in an individual affected with choroid plexus carcinoma meeting Chompret criteria for Li-Fraumeni syndrome (PMCID: PMC9164685) and in at least six individuals affected with breast cancer (PMID: 31081129, 33471991). This variant has been identified in 5/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.329G>C (p.Arg110Pro) and c.329G>T (p.Arg110Leu), are considered to be disease-causing (ClinVar Variation ID: 233627, 406597), suggesting that arginine at this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The TP53 c.328C>T (p.Arg110Cys) variant has been reported in the published literature in individuals with Li-Fraumeni syndrome (PMIDs: 31081129 (2019), 32885271 (2021), and 33471991 (2021)). Functional studies demonstrated that the effect on protein function was inconclusive (PMIDs: 9290701 (1997), 12826609 (2003), 29979965 (2018) and 31081129 (2019)). The frequency of this variant in the general population, 0.00023 (5/21646 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
The TP53 p.Arg110Cys variant was identified in the literature and has been previously reported as a somatic variant but not reported as a germline variant (see examples: Holstege 2009, Pain 2017, Holstege 2010). The variant was also identified in dbSNP (ID: rs587781371) as “With Uncertain significance allele”, in ClinVar (classified as a variant of uncertain significance 4x by Ambry Genetics, Color Genomics, Invitae, and GeneDx), Cosmic (17x somatic entries), and IARC TP53 Database (13 somatic mutations). The variant was not identified in COGR, LOVD 3.0, or the Database of germline p53 mutations. The variant was identified in control databases in 5 of 246096 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the Finnish population in 5 of 22298 chromosomes (freq: 0.000224), but not in the African, Ashkenazi Jewish, East Asian, European (Non-Finnish), Latino, or South Asian populations. The p.Arg110 residue has been classified as a somatic mutational hotspot (Walker et al 1999). Variants at the same amino acid residue have been previously seen and are classified on ClinVar: p.Arg110Pro is classified as likely pathogenic; p.Arg110Leu is classified as likely pathogenic and as a variant of uncertain significance; and p.Arg110Ser and p.Arg110His are both classified as variants of uncertain significance. The p.Arg110 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The p.R110C variant (also known as c.328C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 328. The arginine at codon 110 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in both cases and controls in breast cancer case control studies, and has also been reported in a high-risk breast cancer proband from Sweden (Momozowa Y et al. Nat Commun 2018 10;9(1):4083; Dorling et al. N Engl J Med 2021 02;384:428-439; Kharaziha P et al. Clin Genet 2019 09;96(3):216-225). This variant is in the DNA binding domain of the TP53 protein and is reported to have reduced transactivation capacity compared to wild type (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387; Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8). Two other alterations at this amino acid position, p.R110L and p.R110P, have been detected in individuals with a diagnosis of Li-Fraumeni syndrome (LFS) based on personal and family history (Rines RD et al. Carcinogenesis. 1998 Jun;19(6):979-84; Masciari S et al. Genet Med. 2011 Jul;13(7):651-7). This alteration has been observed in individuals with TP53 related tumors, but not classic Li-Fraumeni syndrome (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 110 of the TP53 protein (p.Arg110Cys). This variant is present in population databases (rs587781371, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 31081129, 32885271; internal data). ClinVar contains an entry for this variant (Variation ID: 142206). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 9290701, 12826609, 29979965, 30224644, 31081129). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22915647, 1655254, 26001148, 22610119, 25148578, 27721458, 15781620, 9290701, 34605602, 26687995, 8690195, 24797764, 25742471, 21118481, 25343854, 17982662, 31081129, 24076587, 23897043, 23894400, 21552135, 21445056, 16778209, 12826609, 11782540, 25952993, 23246812, 22186996, 21519010, 21343334, 20407015, 17606709, 27276561, 29979965, 37352403, 30224644, 36353970, 32885271, 15510160, 30327374, 30613367, 27463065, 27895058, 27959731, 27680515, 26230955)
Comment:
This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 9290701, 12826609, 15781620, 31081129), functional in human cell growth assays (PMID: 29979965, 30224644), and show cytoplasmic and perinuclear localization unlike wild-type protein (PMID: 31081129). This variant has been detected in an individual affected with choroid plexus carcinoma meeting Chompret criteria for Li-Fraumeni syndrome (PMCID: PMC9164685) and in at least six individuals affected with breast cancer (PMID: 31081129, 33471991). This variant has been identified in 5/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.329G>C (p.Arg110Pro) and c.329G>T (p.Arg110Leu), are considered to be disease-causing (ClinVar Variation ID: 233627, 406597), suggesting that arginine at this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Variant summary: TP53 c.328C>T (p.Arg110Cys) results in a non-conservative amino acid change located in the DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes. c.328C>T has been reported in the literature in individuals affected with various cancers without evidence of causality (e.g. Kharaziha_2019, Kobayashi_2018, LernerEllis_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (e.g. Kharaziha_2019). The following publications have been ascertained in the context of this evaluation (PMID: 9290701, 31081129, 30613367, 32885271). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=7) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Comment:
This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 9290701, 12826609, 15781620, 31081129), functional in human cell growth assays (PMID: 29979965, 30224644), and show cytoplasmic and perinuclear localization unlike wild-type protein (PMID: 31081129). This variant has been detected in an individual affected with choroid plexus carcinoma meeting Chompret criteria for Li-Fraumeni syndrome (PMCID: PMC9164685) and in at least six individuals affected with breast cancer (PMID: 31081129, 33471991). This variant has been identified in 5/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.329G>C (p.Arg110Pro) and c.329G>T (p.Arg110Leu), are considered to be disease-causing (ClinVar Variation ID: 233627, 406597), suggesting that arginine at this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The TP53 c.328C>T (p.Arg110Cys) variant has been reported in the published literature in individuals with Li-Fraumeni syndrome (PMIDs: 31081129 (2019), 32885271 (2021), and 33471991 (2021)). Functional studies demonstrated that the effect on protein function was inconclusive (PMIDs: 9290701 (1997), 12826609 (2003), 29979965 (2018) and 31081129 (2019)). The frequency of this variant in the general population, 0.00023 (5/21646 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
The TP53 p.Arg110Cys variant was identified in the literature and has been previously reported as a somatic variant but not reported as a germline variant (see examples: Holstege 2009, Pain 2017, Holstege 2010). The variant was also identified in dbSNP (ID: rs587781371) as “With Uncertain significance allele”, in ClinVar (classified as a variant of uncertain significance 4x by Ambry Genetics, Color Genomics, Invitae, and GeneDx), Cosmic (17x somatic entries), and IARC TP53 Database (13 somatic mutations). The variant was not identified in COGR, LOVD 3.0, or the Database of germline p53 mutations. The variant was identified in control databases in 5 of 246096 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the Finnish population in 5 of 22298 chromosomes (freq: 0.000224), but not in the African, Ashkenazi Jewish, East Asian, European (Non-Finnish), Latino, or South Asian populations. The p.Arg110 residue has been classified as a somatic mutational hotspot (Walker et al 1999). Variants at the same amino acid residue have been previously seen and are classified on ClinVar: p.Arg110Pro is classified as likely pathogenic; p.Arg110Leu is classified as likely pathogenic and as a variant of uncertain significance; and p.Arg110Ser and p.Arg110His are both classified as variants of uncertain significance. The p.Arg110 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
| Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants. | Fortuno C | Human mutation | 2021 | PMID: 33300245 |
| Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
| Functional characterization of novel germline TP53 variants in Swedish families. | Kharaziha P | Clinical genetics | 2019 | PMID: 31081129 |
| A quantitative model to predict pathogenicity of missense variants in the TP53 gene. | Fortuno C | Human mutation | 2019 | PMID: 30840781 |
| Target sequencing of cancer-related genes in early esophageal squamous neoplasia resected by endoscopic resection in Japanese patients. | Kobayashi S | Oncotarget | 2018 | PMID: 30613367 |
| The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
| 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 |
| Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. | Döhner H | Blood | 2017 | PMID: 27895058 |
| The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. | Stengel A | Leukemia | 2017 | PMID: 27680515 |
| TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. | Welch JS | The New England journal of medicine | 2016 | PMID: 27959731 |
| TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. | Kadia TM | Cancer | 2016 | PMID: 27463065 |
| Genomic Classification and Prognosis in Acute Myeloid Leukemia. | Papaemmanuil E | The New England journal of medicine | 2016 | PMID: 27276561 |
| Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival. | Mullany LK | Neoplasia (New York, N.Y.) | 2015 | PMID: 26585234 |
| TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. | Hou HA | Blood cancer journal | 2015 | PMID: 26230955 |
| TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. | Ok CY | Journal of hematology & oncology | 2015 | PMID: 25952993 |
| 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 |
| Functional characterisation of p53 mutants identified in breast cancers with suboptimal responses to anthracyclines or mitomycin. | Berge EO | Biochimica et biophysica acta | 2013 | PMID: 23246812 |
| A novel hierarchical prognostic model of AML solely based on molecular mutations. | Grossmann V | Blood | 2012 | PMID: 22915647 |
| TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. | Rücker FG | Blood | 2012 | PMID: 22186996 |
| TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. | Jädersten M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21519010 |
| Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
| Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
| 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 |
| Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
| 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 |
| Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. | Kato S | Proceedings of the National Academy of Sciences of the United States of America | 2003 | PMID: 12826609 |
| A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. | Friedler A | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11782540 |
| Screening the p53 status of human cell lines using a yeast functional assay. | Jia LQ | Molecular carcinogenesis | 1997 | PMID: 9290701 |
| click to load more citations click to collapse | ||||
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. |
|---|---|---|---|---|
|
Likely oncogenic
criteria provided, single submitter
|
Mar 4, 2025 | RCV004668796.2 |
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. |
|---|
|
Likely oncogenic
(Mar 04, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Neoplasm
Affected status: unknown
Allele origin:
somatic
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094465.2
First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025 |
|
|
Comment:
The p.R110C variant (also known as c.328C>T), located in coding exon 3 of the TP53 gene, results from a C to T substitution at nucleotide position 328. The arginine at codon 110 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in both cases and controls in breast cancer case control studies, and has also been reported in a high-risk breast cancer proband from Sweden (Momozowa Y et al. Nat Commun 2018 10;9(1):4083; Dorling et al. N Engl J Med 2021 02;384:428-439; Kharaziha P et al. Clin Genet 2019 09;96(3):216-225). This variant is in the DNA binding domain of the TP53 protein and is reported to have reduced transactivation capacity compared to wild type (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Additional studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387; Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8). Two other alterations at this amino acid position, p.R110L and p.R110P, have been detected in individuals with a diagnosis of Li-Fraumeni syndrome (LFS) based on personal and family history (Rines RD et al. Carcinogenesis. 1998 Jun;19(6):979-84; Masciari S et al. Genet Med. 2011 Jul;13(7):651-7). This alteration has been observed in individuals with TP53 related tumors, but not classic Li-Fraumeni syndrome (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 110 of the TP53 protein (p.Arg110Cys). This variant is present in population databases (rs587781371, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 31081129, 32885271; internal data). ClinVar contains an entry for this variant (Variation ID: 142206). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 function (PMID: 9290701, 12826609, 29979965, 30224644, 31081129). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22915647, 1655254, 26001148, 22610119, 25148578, 27721458, 15781620, 9290701, 34605602, 26687995, 8690195, 24797764, 25742471, 21118481, 25343854, 17982662, 31081129, 24076587, 23897043, 23894400, 21552135, 21445056, 16778209, 12826609, 11782540, 25952993, 23246812, 22186996, 21519010, 21343334, 20407015, 17606709, 27276561, 29979965, 37352403, 30224644, 36353970, 32885271, 15510160, 30327374, 30613367, 27463065, 27895058, 27959731, 27680515, 26230955)
Comment:
This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function. Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 9290701, 12826609, 15781620, 31081129), functional in human cell growth assays (PMID: 29979965, 30224644), and show cytoplasmic and perinuclear localization unlike wild-type protein (PMID: 31081129). This variant has been detected in an individual affected with choroid plexus carcinoma meeting Chompret criteria for Li-Fraumeni syndrome (PMCID: PMC9164685) and in at least six individuals affected with breast cancer (PMID: 31081129, 33471991). This variant has been identified in 5/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.329G>C (p.Arg110Pro) and c.329G>T (p.Arg110Leu), are considered to be disease-causing (ClinVar Variation ID: 233627, 406597), suggesting that arginine at this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
Variant summary: TP53 c.328C>T (p.Arg110Cys) results in a non-conservative amino acid change located in the DNA-binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251288 control chromosomes. c.328C>T has been reported in the literature in individuals affected with various cancers without evidence of causality (e.g. Kharaziha_2019, Kobayashi_2018, LernerEllis_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity (e.g. Kharaziha_2019). The following publications have been ascertained in the context of this evaluation (PMID: 9290701, 31081129, 30613367, 32885271). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=7) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Comment:
This missense variant replaces arginine with cysteine at codon 110 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown the mutant protein to be partially functional in transactivation assays (PMID: 9290701, 12826609, 15781620, 31081129), functional in human cell growth assays (PMID: 29979965, 30224644), and show cytoplasmic and perinuclear localization unlike wild-type protein (PMID: 31081129). This variant has been detected in an individual affected with choroid plexus carcinoma meeting Chompret criteria for Li-Fraumeni syndrome (PMCID: PMC9164685) and in at least six individuals affected with breast cancer (PMID: 31081129, 33471991). This variant has been identified in 5/251288 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.329G>C (p.Arg110Pro) and c.329G>T (p.Arg110Leu), are considered to be disease-causing (ClinVar Variation ID: 233627, 406597), suggesting that arginine at this position is important for the protein function. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The TP53 c.328C>T (p.Arg110Cys) variant has been reported in the published literature in individuals with Li-Fraumeni syndrome (PMIDs: 31081129 (2019), 32885271 (2021), and 33471991 (2021)). Functional studies demonstrated that the effect on protein function was inconclusive (PMIDs: 9290701 (1997), 12826609 (2003), 29979965 (2018) and 31081129 (2019)). The frequency of this variant in the general population, 0.00023 (5/21646 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Comment:
The TP53 p.Arg110Cys variant was identified in the literature and has been previously reported as a somatic variant but not reported as a germline variant (see examples: Holstege 2009, Pain 2017, Holstege 2010). The variant was also identified in dbSNP (ID: rs587781371) as “With Uncertain significance allele”, in ClinVar (classified as a variant of uncertain significance 4x by Ambry Genetics, Color Genomics, Invitae, and GeneDx), Cosmic (17x somatic entries), and IARC TP53 Database (13 somatic mutations). The variant was not identified in COGR, LOVD 3.0, or the Database of germline p53 mutations. The variant was identified in control databases in 5 of 246096 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). It was observed in the Finnish population in 5 of 22298 chromosomes (freq: 0.000224), but not in the African, Ashkenazi Jewish, East Asian, European (Non-Finnish), Latino, or South Asian populations. The p.Arg110 residue has been classified as a somatic mutational hotspot (Walker et al 1999). Variants at the same amino acid residue have been previously seen and are classified on ClinVar: p.Arg110Pro is classified as likely pathogenic; p.Arg110Leu is classified as likely pathogenic and as a variant of uncertain significance; and p.Arg110Ser and p.Arg110His are both classified as variants of uncertain significance. The p.Arg110 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Citations for somatic classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Functional characterization of novel germline TP53 variants in Swedish families. | Kharaziha P | Clinical genetics | 2019 | PMID: 31081129 |
Text-mined citations for rs587781371 ...
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Record last updated May 17, 2025
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.