chr10-87863705-G-A

Position:

chr10-87863705-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 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:1U:8

Conservation

PhyloP100: 1.84

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE	Protein
PTEN	NM_000314.8 linkuse as main transcript	c.-765G>A	5_prime_UTR_variant	1/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 linkuse as main transcript	c.-245G>A	5_prime_UTR_variant	1/10		NP_001291646.4
PTEN	NM_001304718.2 linkuse as main transcript	c.-1469G>A	5_prime_UTR_variant	1/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.-765G>A		5_prime_UTR_variant	1/9	1	NM_000314.8	ENSP00000361021	P1	P60484-1

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000647

Gnomad4 OTH exome

AF:

0.0000628

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cowden syndrome 1

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2007	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 21, 2017	- -

PTEN hamartoma tumor syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	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 protein 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. -
Uncertain significance, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Jun 18, 2020	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 09, 2023

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. Six ClinVar submitters including an expert panel (ClinGen PTEN Variant Curation Expert Panel) (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Malignant tumor of prostate;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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2019

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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.97

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over