NM_000314.8:c.-765G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: PTEN c.-765G>A (AKA c.-764G>A, NC_000010.10:g.89623462G>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).No criteria currently apply to this variant. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000567/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

PTEN
NM_000314.8 5_prime_UTR

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:8

Conservation

PhyloP100: 1.84

Publications

5 publications found

Variant links:

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

PTEN links:

KLLN (HGNC:37212): (killin, p53 regulated DNA replication inhibitor) The protein encoded by this intronless gene is found in the nucleus, where it can inhibit DNA synthesis and promote S phase arrest coupled to apoptosis. The expression of this DNA binding protein is upregulated by transcription factor p53. [provided by RefSeq, Dec 2012]

KLLN Gene-Disease associations (from GenCC):

Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden syndrome 4
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

KLLN links:

MLDHR (HGNC:55481):

MLDHR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.-765G>A		5_prime_UTR_variant	Exon 1 of 9	ENST00000371953.8	NP_000305.3
KLLN	NM_001126049.2 link	c.-1218C>T		upstream_gene_variant		ENST00000445946.5	NP_001119521.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
PTEN	ENST00000371953.8 link	c.-765G>A	5_prime_UTR_variant	Exon 1 of 9	1	NM_000314.8	ENSP00000361021.3
KLLN	ENST00000445946.5 link	c.-1218C>T	upstream_gene_variant		6	NM_001126049.2	ENSP00000392204.2
MLDHR	ENST00000692337.1 link	c.*51G>A	downstream_gene_variant				ENSP00000509326.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000498

AC:

AN:

241100

Hom.:

Cov.:

AF XY:

0.0000571

AC XY:

AN XY:

122556

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

6882

American (AMR)

AF:

0.00

AC:

AN:

7220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8930

East Asian (EAS)

AF:

0.00

AC:

AN:

22566

South Asian (SAS)

AF:

0.00

AC:

AN:

3010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20756

Middle Eastern (MID)

AF:

0.000790

AC:

AN:

1266

European-Non Finnish (NFE)

AF:

0.0000647

AC:

AN:

154550

Other (OTH)

AF:

0.0000628

AC:

AN:

15920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.555

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000100

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Pathogenic:1Uncertain:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 18, 2020

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

PTEN c.-765G>A (AKA c.-764G>A, NC_000010.10:g.89623462G>A) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). No criteria currently apply to this variant. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant occurs in a non-coding region of the PTEN gene. It does not change the encoded amino acid sequence of the PTEN protein. This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has been observed in individual(s) with PTEN-related conditions (PMID: 12844284, 17847000). This variant is also known as c.-764G/A. ClinVar contains an entry for this variant (Variation ID: 7844). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN function (PMID: 17847000, 25910213). 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. -

Cowden syndrome 1

Pathogenic:1Uncertain:1

Apr 21, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Oct 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

Nov 07, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PTEN c.-765G>A is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 2e-05 in 150850 control chromosomes (gnomAD v3.1.2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.-765G>A has been reported in the literature in individuals affected with Cowden Syndrome (Zhou_2003, Teresi_2007). These reports do not provide unequivocal conclusions about association of the variant with Cowden Syndrome. Experimental evidence evaluating an impact on protein function provided conflicting results: the variant showed an inhibition in luciferase activity when compared to the wild-type, yet luciferase mRNA expression was similar to wild-type suggesting transcription efficiency was not compromised (Teresi_2007). A different study utilizing yeast one-hybrid assays, concluded loss of transcription factor binding and decreased expression (Furman Bass_2015). These studies do not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 25910213, 23315997, 17847000, 12844284). ClinVar contains an entry for this variant (Variation ID: 7844). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Aug 29, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in individuals with breast or endometrial cancer (PMID: 17847000, 12844284); Published functional studies are inconclusive: 60% decrease in luciferase activity, but luciferase mRNA levels similar to wild type; lost protein-DNA interaction and decreased expression by enhanced yeast one-hybrid assay (PMID: 17847000, 25910213); No data available from control populations to assess the frequency of this variant; Describes a nucleotide substitution 765 basepairs upstream of the ATG translational start site in the PTEN promoter region; Also known as c.-764G>A; This variant is associated with the following publications: (PMID: 27569544, 18794875, 23825907, 12844284, 17847000, 23315997, 25910213, 27187382, 34426522) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Oct 22, 2019

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.-764G>A variant is located in the 5' untranslated region (5’ UTR) of the PTEN gene. This variant results from a G to A substitution 764 bases upstream from the first translated codon. This variant has been reported in two individuals (one with endometrial cancer, and one with breast cancer) from cohorts of individuals suspicious for Cowden syndrome (Teresi RE et al. Am. J. Hum. Genet. 2007 Oct;81(4):756-67; Zhou XP et al. Am. J. Hum. Genet. 2003 Aug;73(2):404-11). In one study, reporter assays indicated that this variant demonstrated an approximate 50% decrease in luciferase activity compared to wild type; however, this same study showed that this alteration had no effect on mRNA, suggesting no adverse effects on transcriptional efficiency due to this variant (Teresi et al.) This nucleotide position is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Glioma susceptibility 2

Uncertain:1

Feb 16, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Prostate cancer;C1848599:VACTERL with hydrocephalus;C1854416:Macrocephaly-autism syndrome;C1959582:PTEN hamartoma tumor syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

1.8

PromoterAI

0.0040

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/200

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over