VCV000142916.24 - ClinVar

NM_000546.6(TP53):c.787A>G (p.Asn263Asp)

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.

(9)

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
Uncertain significance(3); Likely benign(6)

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.787A>G (p.Asn263Asp)

Variation ID: 142916 Accession: VCV000142916.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7673833 (GRCh38) [ NCBI UCSC ] 17: 7577151 (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	Feb 19, 2018	May 1, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.787A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Asn263Asp	missense
NM_001126112.3:c.787A>G	NP_001119584.1:p.Asn263Asp	missense
NM_001126113.3:c.787A>G	NP_001119585.1:p.Asn263Asp	missense
NM_001126114.3:c.787A>G	NP_001119586.1:p.Asn263Asp	missense
NM_001126115.2:c.391A>G	NP_001119587.1:p.Asn131Asp	missense
NM_001126116.2:c.391A>G	NP_001119588.1:p.Asn131Asp	missense
NM_001126117.2:c.391A>G	NP_001119589.1:p.Asn131Asp	missense
NM_001126118.2:c.670A>G	NP_001119590.1:p.Asn224Asp	missense
NM_001276695.3:c.670A>G	NP_001263624.1:p.Asn224Asp	missense
NM_001276696.3:c.670A>G	NP_001263625.1:p.Asn224Asp	missense
NM_001276697.3:c.310A>G	NP_001263626.1:p.Asn104Asp	missense
NM_001276698.3:c.310A>G	NP_001263627.1:p.Asn104Asp	missense
NM_001276699.3:c.310A>G	NP_001263628.1:p.Asn104Asp	missense
NM_001276760.3:c.670A>G	NP_001263689.1:p.Asn224Asp	missense
NM_001276761.3:c.670A>G	NP_001263690.1:p.Asn224Asp	missense
NC_000017.11:g.7673833T>C
NC_000017.10:g.7577151T>C
NG_017013.2:g.18718A>G
LRG_321:g.18718A>G
LRG_321t1:c.787A>G	LRG_321p1:p.Asn263Asp
	P04637:p.Asn263Asp

... more HGVS ... less HGVS

Protein change

N131D, N224D, N263D, N104D

Other names

Canonical SPDI

NC_000017.11:7673832:T:C

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.

0.00020 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00011

The Genome Aggregation Database (gnomAD), exomes 0.00011

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Links

ClinGen: CA000419 UniProtKB: P04637#VAR_045310 dbSNP: rs72661119 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	3368	3467

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	Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 11, 2022	RCV000132389.12
Li-Fraumeni syndrome	Likely benign (1)	criteria provided, single submitter	Jan 30, 2024	RCV000474969.15
Li-Fraumeni syndrome 1	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Apr 11, 2023	RCV000663318.7
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Nov 9, 2018	RCV000679373.10

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 (May 15, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000806249.1 First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018
Uncertain significance (Feb 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: paternal	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001482862.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Likely benign (Dec 12, 2019)	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: SCV000686774.4 First in ClinVar: Feb 19, 2018 Last updated: Jan 12, 2022	Comment: This missense variant replaces asparagine with aspartic acid at codon 263 of the TP53 protein. Computational prediction suggests that this variant may not impact protein … (more) This missense variant replaces asparagine with aspartic acid at codon 263 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have shown a partial effect on transcriptional activation of some TP53 target genes (PMID 19558493, 12826609), however the variant was neutral in human cell apoptosis, proliferation and growth suppression assays (PMID 24076587, 29979965, 30224644). This variant has been reported in two South Asian individuals affected with breast cancer in the literature (PMID 24929325, 26225655), but also in several apparently unaffected South Asian control samples (PMID 28861920). This variant has been identified in 28/246378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 25/30148 of these alleles are from South Asian ancestry suggesting that this variant is a polymorphism in this population. Based on the available evidence, this variant is classified as Likely Benign. (less)
Likely benign (May 31, 2018)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000786588.2 First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018	Publications: PubMed (5) PubMed: 24929325‚ 24076587‚ 12826609‚ 26225655‚ 28861920
Likely benign (Nov 09, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001777573.1 First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021	Comment: This variant is associated with the following publications: (PMID: 30840781, 29470806, 19558493, 30352134, 28861920, 24929325, 21643842, 24076587, 12826609, 12909720, 29979965, 26225655)
Likely benign (Feb 11, 2022)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002532711.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Uncertain significance (Apr 11, 2023)	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: SCV004017861.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Likely benign (Jan 30, 2024)	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: SCV000545267.10 First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024	Publications: PubMed (1) PubMed: 28492532
Likely benign (Mar 18, 2019)	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: SCV000187481.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 12826609‚ 19558493 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)

Comment:

This missense variant replaces asparagine with aspartic acid at codon 263 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have shown a partial effect on transcriptional activation of some TP53 target genes (PMID 19558493, 12826609), however the variant was neutral in human cell apoptosis, proliferation and growth suppression assays (PMID 24076587, 29979965, 30224644). This variant has been reported in two South Asian individuals affected with breast cancer in the literature (PMID 24929325, 26225655), but also in several apparently unaffected South Asian control samples (PMID 28861920). This variant has been identified in 28/246378 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 25/30148 of these alleles are from South Asian ancestry suggesting that this variant is a polymorphism in this population. Based on the available evidence, this variant is classified as Likely Benign.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history.	de Andrade KC	Human mutation	2017	PMID: 28861920
Targeted Resequencing of 30 Genes Improves the Detection of Deleterious Mutations in South Indian Women with Breast and/or Ovarian Cancers.	Rajkumar T	Asian Pacific journal of cancer prevention : APJCP	2015	PMID: 26225655
Germline mutations of TP53 gene in breast cancer.	Damineni S	Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine	2014	PMID: 24929325
Mapping the p53 transcriptome universe using p53 natural polymorphs.	Wang B	Cell death and differentiation	2014	PMID: 24076587
Investigation and prediction of the severity of p53 mutants using parameters from structural calculations.	Carlsson J	The FEBS journal	2009	PMID: 19558493
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

Text-mined citations for rs72661119 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000546.6(TP53):c.787A>G (p.Asn263Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs72661119 ...