VCV000232289.13 - ClinVar

NM_000546.6(TP53):c.764T>A (p.Ile255Asn)

Germline

Classification

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.

(13)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000546.6(TP53):c.764T>A (p.Ile255Asn)

Variation ID: 232289 Accession: VCV000232289.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7577517 (GRCh37) [ NCBI UCSC ] 17: 7674199 (GRCh38) [ 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	May 29, 2016	Sep 16, 2024	Feb 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.764T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Ile255Asn	missense
NM_001126112.3:c.764T>A	NP_001119584.1:p.Ile255Asn	missense
NM_001126113.3:c.764T>A	NP_001119585.1:p.Ile255Asn	missense
NM_001126114.3:c.764T>A	NP_001119586.1:p.Ile255Asn	missense
NM_001126115.2:c.368T>A	NP_001119587.1:p.Ile123Asn	missense
NM_001126116.2:c.368T>A	NP_001119588.1:p.Ile123Asn	missense
NM_001126117.2:c.368T>A	NP_001119589.1:p.Ile123Asn	missense
NM_001126118.2:c.647T>A	NP_001119590.1:p.Ile216Asn	missense
NM_001276695.3:c.647T>A	NP_001263624.1:p.Ile216Asn	missense
NM_001276696.3:c.647T>A	NP_001263625.1:p.Ile216Asn	missense
NM_001276697.3:c.287T>A	NP_001263626.1:p.Ile96Asn	missense
NM_001276698.3:c.287T>A	NP_001263627.1:p.Ile96Asn	missense
NM_001276699.3:c.287T>A	NP_001263628.1:p.Ile96Asn	missense
NM_001276760.3:c.647T>A	NP_001263689.1:p.Ile216Asn	missense
NM_001276761.3:c.647T>A	NP_001263690.1:p.Ile216Asn	missense
NC_000017.11:g.7674199A>T
NC_000017.10:g.7577517A>T
NG_017013.2:g.18352T>A
LRG_321:g.18352T>A
LRG_321t1:c.764T>A	LRG_321p1:p.Ile255Asn
	P04637:p.Ile255Asn

... more HGVS ... less HGVS

Protein change

I123N, I216N, I255N, I96N

Other names

Canonical SPDI

NC_000017.11:7674198:A:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

Links

ClinGen: CA10580923 UniProtKB: P04637#VAR_045276 dbSNP: rs876659675 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	3367	3466

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jun 18, 2022	RCV000221023.7
B-cell chronic lymphocytic leukemia	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000422868.3
Glioblastoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000425285.3
Pancreatic adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000432486.3
Carcinoma of esophagus	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000433813.3
Breast neoplasm	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000432689.3
Lung adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000440110.3
Neoplasm of brain	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000441998.3
Li-Fraumeni syndrome	Uncertain significance (1)	criteria provided, single submitter	Aug 4, 2023	RCV000633370.9
Li-Fraumeni syndrome 1	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Feb 16, 2024	RCV002288875.4
not provided	Likely pathogenic (1)	criteria provided, single submitter	Dec 15, 2023	RCV004701291.1
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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 (Jan 12, 2021)	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: SCV000276382.7 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Comment: The p.I255N pathogenic mutation (also known as c.764T>A), located in coding exon 6 of the TP53 gene, results from a T to A substitution at … (more) The p.I255N pathogenic mutation (also known as c.764T>A), located in coding exon 6 of the TP53 gene, results from a T to A substitution at nucleotide position 764. The isoleucine at codon 255 is replaced by asparagine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Uncertain significance (Jun 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002582005.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Uncertain significance (Jun 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002582002.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Uncertain significance (Aug 04, 2023)	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: SCV000754592.4 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 12826609‚ 29979965‚ 30224644 Comment: This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 255 of the TP53 protein (p.Ile255Asn). … (more) This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 255 of the TP53 protein (p.Ile255Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. 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. This variant disrupts the p.Ile255 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 232289). (less)
Likely pathogenic (Feb 16, 2024)	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: SCV004932239.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 29979965 Comment: This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad … (more) This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. (less)
Likely pathogenic (Dec 15, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV005201303.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression ability and a dominant negative effect (PMID: 12826609, 30224644, 29979965); Not observed … (more) Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression ability and a dominant negative effect (PMID: 12826609, 30224644, 29979965); Not observed at significant frequency in large population cohorts (gnomAD); 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: 27884971, 26230955, 26781615, 20876136, 28665052, 30224644, 29979965, 15510160, 12826609) (less)
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000508703.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000359597:c.764T>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Carcinoma of esophagus (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000508702.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000359597:c.764T>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Glioblastoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000508707.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000359597:c.764T>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	B-cell chronic lymphocytic leukemia (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000508704.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000359597:c.764T>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Breast neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000508705.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000359597:c.764T>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Pancreatic adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000508708.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000359597:c.764T>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of brain (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000508706.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000359597:c.764T>A
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Comment:

The p.I255N pathogenic mutation (also known as c.764T>A), located in coding exon 6 of the TP53 gene, results from a T to A substitution at nucleotide position 764. The isoleucine at codon 255 is replaced by asparagine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 255 of the TP53 protein (p.Ile255Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. 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. This variant disrupts the p.Ile255 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 232289).

Comment:

Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression ability and a dominant negative effect (PMID: 12826609, 30224644, 29979965); Not observed at significant frequency in large population cohorts (gnomAD); 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: 27884971, 26230955, 26781615, 20876136, 28665052, 30224644, 29979965, 15510160, 12826609)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.	Chang MT	Nature biotechnology	2016	PMID: 26619011
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
http://docm.genome.wustl.edu/variants/ENST00000359597:c.764T>A	-	-	-	-

Text-mined citations for rs876659675 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000546.6(TP53):c.764T>A (p.Ile255Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs876659675 ...