10-87960922-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP2PP3PM2_SupportingPS3_ModeratePM6_StrongPS4_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000314.8(PTEN):c.830C>T (p.Thr277Ile) variant meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (PMID:25549896 and internal laboratory contributor).PS3_M: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID:29706350.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.PP3: REVEL score > 0.7 (score=0.988)PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID:25549896). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000207/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Failed GnomAD Quality Control

Consequence

PTEN
NM_000314.8 missense

Scores

13

4

2

Clinical Significance

Pathogenic reviewed by expert panel P:6O:1

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]

PTEN links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM6

For more information check the summary or visit ClinGen Evidence Repository.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.830C>T	p.Thr277Ile	missense_variant	Exon 8 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.1349C>T	p.Thr450Ile	missense_variant	Exon 9 of 10		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.239C>T	p.Thr80Ile	missense_variant	Exon 8 of 9		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.830C>T	p.Thr277Ile	missense_variant	Exon 8 of 9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

0

AN:

144834

Hom.:

0

Cov.:

31

FAILED QC

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

Cov.:

36

GnomAD4 genome

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

AF:

0.00

AC:

0

AN:

144834

Hom.:

0

Cov.:

31

AF XY:

0.00

AC XY:

0

AN XY:

69962

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 03, 2024	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 277 of the PTEN protein (p.Thr277Ile). 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: 25549896). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 184277). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTEN protein function with a positive predictive value of 80%. This variant disrupts the p.Thr277 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28263967; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Jun 14, 2023	NM_000314.8(PTEN):c.830C>T (p.Thr277Ile) variant meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (PMID:25549896 and internal laboratory contributor). PS3_M: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350. 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. PP3: REVEL score > 0.7 (score=0.988) PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID: 25549896). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 29, 2024

Published functional studies demonstrate reduced lipid phosphatase activity (PMID: 29706350); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25549896, 34663891, 32123317, 29706350, 18626510) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The p.T277I variant (also known as c.830C>T), located in coding exon 8 of the PTEN gene, results from a C to T substitution at nucleotide position 830. The threonine at codon 277 is replaced by isoleucine, an amino acid with some similar properties. This variant was reported as de novo (unconfirmed parentage) in a female child followed from birth to age 4 who presented with macrocephaly followed by patent ductus arteriosus, nevus flammeus of the philtrum suggestive of Megalencephaly-Capillary Malformation syndrome, overgrowth, widespread capillary malformations, enlarged cerebral ventricles identified by MRI and speech support was needed for learning disabilities (Busa T et al. Eur J Paediatr Neurol, 2015 Mar;19:188-92). This variant was reported as de novo (unconfirmed parentage) in an additional individual with features consistent with PTEN tumor hamartoma syndrome (external communication). In addition, RNA studies were performed for this variant and no abnormal splicing was reported to be associated (Wai HA et al. Genet Med, 2020 Jun;22:1005-1014). However, in a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was reported to be in the hypomorphic range of functionally abnormal (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Cowden syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Feb 14, 2020

ClinGen PTEN Expert Panel Specification v2 used for classification. Data included in classification: UK family #1: Paediatric phenotype specificity score 3 (extreme macrocephaly + 2 (autism/dev delay)=5. Literature case #1 Busa et al, 2015 (PMID: 25549896): Paediatric phenotype specificity score 3 (extreme macrocephaly) + 2 (enlarged cerebral ventricles)=5. 2 probands with paediatric specificity score of 5=2 points (PS4_mod). The variant was absent from the gnomAD population (141,456 individuals) (PM2_mod). Literature case #1: de novo in proband (PM6_mod). ExAC constraint score: 3.71, gnomAD constraint score: 3.49 i.e. low benign missense rate (PP2_sup). Data not included in classification: In silico: Revel score 0.988. The variant is in protein domains: Tensin phosphatase, C2 domain, Bifunctional phosphatidylinositol trisphosphate phosphatase/dual specificity phosphatase PTEN C2 domain. -

Macrocephaly-autism syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 16, 2024

Criteria applied: PS4_MOD,PS2_MOD,PM5,PM2_SUP,PP3,PP2 -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Mar 04, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.54

D

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

29

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.75

D

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Pathogenic

0.87

D

PROVEAN

Pathogenic

-5.7

D;.

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.82

P;.

Vest4

0.95

MutPred

0.83

Loss of disorder (P = 0.1174);.;

MVP

0.99

MPC

2.4

ClinPred

0.99

D

GERP RS

5.1

Varity_R

0.90

gMVP

0.98

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

LitVar

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

Other links and lift over

dbSNP: rs398123329; hg19: chr10-89720679; COSMIC: COSV64291992;