VCV000184863.17 - ClinVar

NM_000546.6(TP53):c.413C>T (p.Ala138Val)

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.

(5)

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(1); Uncertain significance(2)

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.413C>T (p.Ala138Val)

Variation ID: 184863 Accession: VCV000184863.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p13.1 17: 7675199 (GRCh38) [ NCBI UCSC ] 17: 7578517 (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	Nov 3, 2018	May 1, 2024	Feb 13, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.413C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000537.3:p.Ala138Val	missense
NM_001126112.3:c.413C>T	NP_001119584.1:p.Ala138Val	missense
NM_001126113.3:c.413C>T	NP_001119585.1:p.Ala138Val	missense
NM_001126114.3:c.413C>T	NP_001119586.1:p.Ala138Val	missense
NM_001126115.2:c.17C>T	NP_001119587.1:p.Ala6Val	missense
NM_001126116.2:c.17C>T	NP_001119588.1:p.Ala6Val	missense
NM_001126117.2:c.17C>T	NP_001119589.1:p.Ala6Val	missense
NM_001126118.2:c.296C>T	NP_001119590.1:p.Ala99Val	missense
NM_001276695.3:c.296C>T	NP_001263624.1:p.Ala99Val	missense
NM_001276696.3:c.296C>T	NP_001263625.1:p.Ala99Val	missense
NM_001276697.3:c.-65C>T		5 prime UTR
NM_001276698.3:c.-65C>T		5 prime UTR
NM_001276699.3:c.-65C>T		5 prime UTR
NM_001276760.3:c.296C>T	NP_001263689.1:p.Ala99Val	missense
NM_001276761.3:c.296C>T	NP_001263690.1:p.Ala99Val	missense
NC_000017.11:g.7675199G>A
NC_000017.10:g.7578517G>A
NG_017013.2:g.17352C>T
LRG_321:g.17352C>T
LRG_321t1:c.413C>T	LRG_321p1:p.Ala138Val
	P04637:p.Ala138Val

... more HGVS ... less HGVS

Protein change

A138V, A6V, A99V

Other names

Canonical SPDI

NC_000017.11:7675198:G:A

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.

Exome Aggregation Consortium (ExAC) 0.00001

Links

dbSNP: rs750600586 ClinGen: CA000168 UniProtKB: P04637#VAR_033034 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	3404	3504

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 pathogenic (1)	criteria provided, single submitter	Mar 7, 2023	RCV000164195.6
Li-Fraumeni syndrome	Uncertain significance (1)	criteria provided, single submitter	Sep 21, 2023	RCV000813957.7
Adrenocortical carcinoma, hereditary	Uncertain significance (1)	criteria provided, single submitter	Apr 6, 2022	RCV003474852.1
Li-Fraumeni syndrome 1	Pathogenic (1)	criteria provided, single submitter	Feb 13, 2024	RCV004019963.1
Adrenal cortex carcinoma	Likely pathogenic (1)	no assertion criteria provided	-	RCV003995323.1

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 (Apr 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Adrenocortical carcinoma, hereditary Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004204281.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Likely pathogenic (Mar 07, 2023)	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: SCV000214816.7 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Publications: PubMed (9) PubMed: 11152481‚ 12826609‚ 15580553‚ 18413811‚ 22507745‚ 29979965‚ 30224644‚ 33471991‚ 7761089 Comment: The p.A138V variant (also known as c.413C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide … (more) The p.A138V variant (also known as c.413C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 413. The alanine at codon 138 is replaced by valine, an amino acid with similar properties. This alteration was detected in a Chinese breast cancer patient diagnosed at 33y as well as her sister affected with breast cancer at 33y and uterine leimyosarcoma at 43y (Lee DS, Breast Cancer Res. 2012 ; 14(2):R66). Analysis of a breast tumor from this family did demonstrate TP53 LOH associated with this alteration. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially reduced transactivation capacity compared to wild type 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 (Zhao K et al, 2001 Apr;276:12120-7). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Uncertain significance (Sep 21, 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: SCV000954344.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024	Publications: PubMed (10) PubMed: 7761089‚ 12826609‚ 20407015‚ 22923379‚ 27533082‚ 27657329‚ 29979965‚ 30224644‚ 22507745‚ 32552660 Comment: 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 … (more) 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 7761089, 12826609, 20407015, 22923379, 27533082, 27657329, 29979965, 30224644). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 184863). This missense change has been observed in individual(s) with breast cancer, pancreatic cancer, sarcoma, and/or stomach cancer (PMID: 22507745, 32552660). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 138 of the TP53 protein (p.Ala138Val). (less)
Pathogenic (Feb 13, 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: SCV004931397.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 7761089‚ 7624116‚ 22507745 Comment: This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7761089, 7624116]. This variant has been reported in multiple individuals with … (more) This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7761089, 7624116]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22507745]. (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	Adrenocortical carcinoma Affected status: no Allele origin: somatic	Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University Accession: SCV004046829.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024

Comment:

The p.A138V variant (also known as c.413C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 413. The alanine at codon 138 is replaced by valine, an amino acid with similar properties. This alteration was detected in a Chinese breast cancer patient diagnosed at 33y as well as her sister affected with breast cancer at 33y and uterine leimyosarcoma at 43y (Lee DS, Breast Cancer Res. 2012 ; 14(2):R66). Analysis of a breast tumor from this family did demonstrate TP53 LOH associated with this alteration. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially reduced transactivation capacity compared to wild type 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 (Zhao K et al, 2001 Apr;276:12120-7). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Comment:

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. Experimental studies have shown that this missense change affects TP53 function (PMID: 7761089, 12826609, 20407015, 22923379, 27533082, 27657329, 29979965, 30224644). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 184863). This missense change has been observed in individual(s) with breast cancer, pancreatic cancer, sarcoma, and/or stomach cancer (PMID: 22507745, 32552660). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 138 of the TP53 protein (p.Ala138Val).

Comment:

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7761089, 7624116]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22507745].

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
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
A novel hotspot and rare somatic mutation p.A138V, at TP53 is associated with poor survival of pancreatic ductal and periampullary adenocarcinoma patients.	Saha G	Molecular medicine (Cambridge, Mass.)	2020	PMID: 32552660
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
Phosphorylation of Def Regulates Nucleolar p53 Turnover and Cell Cycle Progression through Def Recruitment of Calpain3.	Guan Y	PLoS biology	2016	PMID: 27657329
Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells.	Menendez D	Oncotarget	2016	PMID: 27533082
Rapid profiling of disease alleles using a tunable reporter of protein misfolding.	Pittman AM	Genetics	2012	PMID: 22923379
Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients.	Lee DS	Breast cancer research : BCR	2012	PMID: 22507745
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.	Jordan JJ	Molecular cancer research : MCR	2010	PMID: 20407015
WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells.	Cuddihy AR	Molecular cancer therapeutics	2008	PMID: 18413811
Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations.	Soussi T	Human mutation	2005	PMID: 15580553
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
Crystal structure of the mouse p53 core DNA-binding domain at 2.7 A resolution.	Zhao K	The Journal of biological chemistry	2001	PMID: 11152481
A temperature sensitive mutant of the human p53, Val138, arrests rat cell growth without induced expression of cip1/waf1/sdi1 after temperature shift-down.	Hirano Y	Oncogene	1995	PMID: 7761089
A human temperature-sensitive p53 mutant p53Val-138: modulation of the cell cycle, viability and expression of p53-responsive genes.	Yamato K	Oncogene	1995	PMID: 7624116
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Text-mined citations for rs750600586 ...

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.413C>T (p.Ala138Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs750600586 ...