VCV000127666.7 - ClinVar

NM_000314.6(PTEN):c.-1243G>A

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.

(3)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000314.6(PTEN):c.-1243G>A

Variation ID: 127666 Accession: VCV000127666.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.31 10: 87863226 (GRCh38) [ NCBI UCSC ] 10: 89622983 (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	Dec 19, 2017	May 1, 2024	Jul 12, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001126049.2:c.-739C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		5 prime UTR
NC_000010.11:g.87863226G>A
NC_000010.10:g.89622983G>A
NG_007466.2:g.4789G>A
NG_033079.1:g.5212C>T
LRG_1087:g.5212C>T
LRG_1087t1:c.-739C>T
LRG_311:g.4789G>A
LRG_311t1:c.-1243G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000010.11:87863225: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.

Links

ClinGen: CA151482 dbSNP: rs727502790 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.
PTEN		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	3102	3612
KLLN		-	-	GRCh38 GRCh38 GRCh37	21	365

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	Uncertain significance (1)	criteria provided, single submitter	Jun 10, 2022	RCV000115561.18
PTEN-related disorder	Uncertain significance (1)	criteria provided, single submitter	Jul 12, 2023	RCV004529931.1
not provided	Uncertain significance (1)	criteria provided, single submitter	Dec 31, 2021	RCV003477495.1

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 (Jul 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	PTEN-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004117998.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The PTEN c.-1243G>A variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant … (more) The PTEN c.-1243G>A variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-89622984-G-A) and is reported in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/189522/). Of note, other variants in the PTEN promoter region have been reported to be associated with Cowden syndrome (Zhou et al. 2003. PubMed ID: 12844284). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
Uncertain significance (Jun 10, 2022)	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: SCV000187616.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 25669429 Comment: The c.-1243G>A variant is located in the 5' untranslated region (5'UTR) of the PTEN gene. This variant results from a G to A substitution 1243 … (more) The c.-1243G>A variant is located in the 5' untranslated region (5'UTR) of the PTEN gene. This variant results from a G to A substitution 1243 nucleotides upstream from the first translated codon. This variant is located in the promoter region of the PTEN gene, but its potential impact on PTEN regulation has not yet been investigated (Zhou XP et al. Am. J. Hum. Genet. 2003 Aug;73:404-11). This variant, referred to as c.-1242G>A, has been detected in a cohort of patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43). This nucleotide position is highly conserved on limited sequence alignment. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (Dec 31, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004219130.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: The variant has not been reported in individuals with PTEN-related conditions in the published literature. The frequency of this variant in the general population, 0.00034 … (more) The variant has not been reported in individuals with PTEN-related conditions in the published literature. The frequency of this variant in the general population, 0.00034 (23/68022 chromosomes in European (non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant. (less)

Comment:

The PTEN c.-1243G>A variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-89622984-G-A) and is reported in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/189522/). Of note, other variants in the PTEN promoter region have been reported to be associated with Cowden syndrome (Zhou et al. 2003. PubMed ID: 12844284). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Comment:

The c.-1243G>A variant is located in the 5' untranslated region (5'UTR) of the PTEN gene. This variant results from a G to A substitution 1243 nucleotides upstream from the first translated codon. This variant is located in the promoter region of the PTEN gene, but its potential impact on PTEN regulation has not yet been investigated (Zhou XP et al. Am. J. Hum. Genet. 2003 Aug;73:404-11). This variant, referred to as c.-1242G>A, has been detected in a cohort of patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43). This nucleotide position is highly conserved on limited sequence alignment. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

The variant has not been reported in individuals with PTEN-related conditions in the published literature. The frequency of this variant in the general population, 0.00034 (23/68022 chromosomes in European (non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant.

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
KLLN epigenotype-phenotype associations in Cowden syndrome.	Nizialek EA	European journal of human genetics : EJHG	2015	PMID: 25669429

Text-mined citations for rs727502790 ...

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_000314.6(PTEN):c.-1243G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs727502790 ...