10-87894049-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS2PS3PM2PP2

This summary comes from the ClinGen Evidence Repository: PTEN c.104T>G (p.Met35Arg) meets criteria to be classified as pathogenic 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).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (PMID 9425889)PS3: Phosphatase activity <50% of wild type. (PMID 21828076, 25875300)PM2: Absent in large sequenced populations (PMID 27535533).PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000268/MONDO:0017623/003

Frequency

Genomes: not found (cov: 32)

Consequence

PTEN
NM_000314.8 missense

Scores

15
3
1

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 7.53
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS2
For more information check the summary or visit ClinGen Evidence Repository.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP2
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PTENNM_000314.8 linkc.104T>G p.Met35Arg missense_variant 2/9 ENST00000371953.8 NP_000305.3
PTENNM_001304717.5 linkc.623T>G p.Met208Arg missense_variant 3/10 NP_001291646.4 P60484
PTENNM_001304718.2 linkc.-602T>G 5_prime_UTR_variant 2/9 NP_001291647.1 P60484

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTENENST00000371953.8 linkc.104T>G p.Met35Arg missense_variant 2/91 NM_000314.8 ENSP00000361021.3 P60484-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Cowden syndrome 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Nov 06, 2023This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29785012]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 37819013, 9425889]. -
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2003- -
PTEN hamartoma tumor syndrome Pathogenic:2
Pathogenic, reviewed by expert panelcurationClingen PTEN Variant Curation Expert Panel, ClingenJul 25, 2018PTEN c.104T>G (p.Met35Arg) meets criteria to be classified as pathogenic 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (PMID 9425889) PS3: Phosphatase activity <50% of wild type. (PMID 21828076, 25875300) PM2: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 09, 2024This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 35 of the PTEN protein (p.Met35Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 9425889). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7825). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 21828076, 25875300). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Met35 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 17526801, 26468640; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
34
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.97
D
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.88
D
MetaRNN
Pathogenic
1.0
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
H
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-5.8
D
REVEL
Pathogenic
0.99
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.99
MutPred
0.97
Loss of sheet (P = 0.0315);
MVP
1.0
MPC
4.9
ClinPred
1.0
D
GERP RS
5.2
Varity_R
0.97
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.37
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.37
Position offset: 1

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.

Other links and lift over

dbSNP: rs121909225; hg19: chr10-89653806; COSMIC: COSV64292490; API