10-87960914-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM5PP2PP3_Strong

The NM_000314.8(PTEN):c.822G>T(p.Trp274Cys) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W274L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.56

Publications

1 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 Gene-Disease associations (from GenCC):

Cowden syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
PTEN hamartoma tumor syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
macrocephaly-autism syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
renal cell carcinoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
leiomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
activated PI3K-delta syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Bannayan-Riley-Ruvalcaba syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Lhermitte-Duclos disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Proteus-like syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
glioma susceptibility 2
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

PTEN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 34 uncertain in NM_000314.8

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-87960913-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 427600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the PTEN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 3.4883 (above the threshold of 3.09). Trascript score misZ: 4.1129 (above the threshold of 3.09). GenCC associations: The gene is linked to leiomyosarcoma, renal cell carcinoma, Cowden syndrome 1, macrocephaly-autism syndrome, glioma susceptibility 2, PTEN hamartoma tumor syndrome, Cowden disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, activated PI3K-delta syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PTEN	NM_000314.8 link	c.822G>T	p.Trp274Cys	missense_variant	Exon 8 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.1341G>T	p.Trp447Cys	missense_variant	Exon 9 of 10		NP_001291646.4
PTEN	NM_001304718.2 link	c.231G>T	p.Trp77Cys	missense_variant	Exon 8 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.822G>T	p.Trp274Cys	missense_variant	Exon 8 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

146144

Hom.:

Cov.:

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:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1454526

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723242

African (AFR)

AF:

0.00

AC:

AN:

33054

American (AMR)

AF:

0.00

AC:

AN:

43990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25912

East Asian (EAS)

AF:

0.00

AC:

AN:

39494

South Asian (SAS)

AF:

0.00

AC:

AN:

84320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108772

Other (OTH)

AF:

0.00

AC:

AN:

59990

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

146144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70842

African (AFR)

AF:

0.00

AC:

AN:

39216

American (AMR)

AF:

0.00

AC:

AN:

14738

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3432

East Asian (EAS)

AF:

0.00

AC:

AN:

5084

South Asian (SAS)

AF:

0.00

AC:

AN:

4694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8876

Middle Eastern (MID)

AF:

0.00

AC:

AN:

298

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66880

Other (OTH)

AF:

0.00

AC:

AN:

2022

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Uncertain:1

Sep 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 274 of the PTEN protein (p.Trp274Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PTEN protein function with a negative predictive value of 80%. 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.83

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

3.3

M;.

PhyloP100

9.6

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-12

D;.

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.91

ClinPred

1.0

GERP RS

5.1

Varity_R

0.97

gMVP

0.99

Mutation Taster

=4/96

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over