rs562015640

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_000314.8(PTEN):c.865A>G(p.Lys289Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K289R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 8.85

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_000314.8

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, PTEN

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PTEN	NM_000314.8 linkuse as main transcript	c.865A>G	p.Lys289Glu	missense_variant	8/9	ENST00000371953.8
PTEN	NM_001304717.5 linkuse as main transcript	c.1384A>G	p.Lys462Glu	missense_variant	9/10
PTEN	NM_001304718.2 linkuse as main transcript	c.274A>G	p.Lys92Glu	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.865A>G	p.Lys289Glu	missense_variant	8/9	1	NM_000314.8	P1	P60484-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151878

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251050

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000205

AC:

AN:

1461588

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727104

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:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 27, 2022

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 PTEN function (PMID: 17218261, 18716620, 26216063). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). ClinVar contains an entry for this variant (Variation ID: 142912). This missense change has been observed in individual(s) with clinical features of PTEN hamartoma tumor syndrome (PMID: 9797362). This variant is present in population databases (rs562015640, gnomAD 0.006%). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 289 of the PTEN protein (p.Lys289Glu). -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2023

The p.K289E variant (also known as c.865A>G), located in coding exon 8 of the PTEN gene, results from an A to G substitution at nucleotide position 865. The lysine at codon 289 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in one study in individuals with clinical features of PTEN hamartoma tumor syndrome and segregated with disease in two affected family members. The authors also reported PTEN loss of heterozygosity (LOH) in gastrointestinal polyps of various histopathologic types; however, only germline PTEN testing was performed and other genes associated with polyposis syndromes were excluded (Chi SG et al. Gastroenterology 1998; 115:1084-9). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally neutral (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This variant also demonstrated "possibly wild type-like" intracellular protein abundance in another massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). Based on internal structural analysis, K289E disrupts a known ubiquitination site in the PTEN C2 domain which may play a role in nuclear transport (Ambry internal data). In addition, several studies report that this variant retains its phosphatase activity, but demonstrates a nuclear import/export defect with reduced nuclear shuttling (Georgescu MM et al. Cancer Res. 2000; 60:7033-8; Trotman LC et al. Cell 2007; 128:141-56; Wang X et al. Cell 2007; 128:129-39; Song MS et al. Nature 2008; 455:813-7). However, the role of defective nuclear shuttling in tumorigenesis is currently unclear and other functional studies have shown that PTEN K289E is able to localize to the nucleus similarly to wild type PTEN in HEK293 cells (Bassi C et al. Science, 2013 Jul;341:395-9; Nguyen HN et al. Sci Rep, 2015 Jul;5:12600). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

D;.

Eigen

Benign

0.045

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.055

MetaRNN

Uncertain

0.48

T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.34

N;.

REVEL

Uncertain

0.52

Sift

Benign

0.62

T;.

Sift4G

Benign

0.91

T;T

Polyphen

0.0070

B;.

Vest4

0.75

MutPred

0.51

Loss of ubiquitination at K289 (P = 0.0063);.;

MVP

0.99

MPC

1.6

ClinPred

0.66

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.77

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