rs587782580

chr10-87863704-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000314.8(PTEN):c.-766G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0900

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.-766G>A		5_prime_UTR_variant	1/9	ENST00000371953.8
PTEN	NM_001304717.5	c.-246G>A		5_prime_UTR_variant	1/10
PTEN	NM_001304718.2	c.-1470G>A		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.-766G>A		5_prime_UTR_variant	1/9	1	NM_000314.8	P1
	ENST00000692337.1			downstream_gene_variant				P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 241082 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 122542

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2023

The PTEN c.-765G>A variant is located in the 5' untranslated region. This variant (also referred to as -764A-G, c.-764G>A, and -764G/A using alternative nomenclature) occurs in the pre-coding region of the gene. This variant has been identified in individuals affected with Cowden syndrome who also had breast or endometrial cancer (Zhou et al. 2003. PubMed ID: 12844284; Teresi et al. 2007. PubMed ID: 17847000). In a reporter assay, this variant demonstrated ~50% decrease in luciferase activity compared to wild type; however, luciferase mRNA expression was equal to that of wild type in cells transfected with the wild type construct (Teresi et al. 2007. PubMed ID: 17847000). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as uncertain by an expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/7844/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2019

The c.-765G>A variant is located in the 5' untranslated region (5’UTR) of the PTEN gene. This variant results from a G to A substitution 765 nucleotides upstream from the first translated codon. In one study, this variant was described in an individual with breast cancer (Zhou XP et al. Am J Hum Genet. 2003;73(2):404-411). In another study, this variant was described in a patient with benign breast neoplasia and endometrial cancer (Teresi RE et al. Am. J. Hum. Genet. 2007 Oct;81(4):756-67). This same study demonstrates that PTEN transcription efficiency and mRNA stability were not compromised, although the c.-765G>A alteration did result in a decrease of luciferase activity as measured by an in vitro reporter assay. In addition, in silico analysis predicted that the mRNA secondary structure of the PTEN promoter was altered. Based on the above evidence, the authors hypothesized that the c.-765G>A variant would result in a significant decrease in protein expression. Of note, this variant is also known as -764G>A in published literature. In addition, this nucleotide position is highly conserved in available vertebrate species. Since supporting evidence for this variant is limited at this time, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	18
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)		0.040		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

Other links and lift over

dbSNP: rs587782580; hg19: chr10-89623461;