10-87864583-C-T

Position:

chr10-87864583-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS3BS1

This summary comes from the ClinGen Evidence Repository: PTEN c.79+35C>T (IVS1+35C>T) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).BS1: Allele frequency of 0.00178 (1.78%, 492/277,200 alleles) in the gnomAD cohort. (PMID 27535533) BS3: Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 17636424) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000576/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 11 hom. )

Consequence

PTEN
NM_000314.8 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 3.15

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 Benign. Variant got -8 ACMG points.

BS1

BS3

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
PTEN	NM_000314.8 linkuse as main transcript	c.79+35C>T	intron_variant	ENST00000371953.8
PTEN	NM_001304717.5 linkuse as main transcript	c.598+35C>T	intron_variant
PTEN	NM_001304718.2 linkuse as main transcript	c.-626+35C>T	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.79+35C>T		intron_variant		1	NM_000314.8	P1	P60484-1

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

207

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00198

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00193

AC:

486

AN:

251392

Hom.:

AF XY:

0.00215

AC XY:

292

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00257

Gnomad ASJ exome

AF:

0.000694

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00343

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00198

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00224

AC:

3228

AN:

1441812

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

1613

AN XY:

718614

show subpopulations

Gnomad4 AFR exome

AF:

0.000485

Gnomad4 AMR exome

AF:

0.00273

Gnomad4 ASJ exome

AF:

0.000807

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00409

Gnomad4 FIN exome

AF:

0.00135

Gnomad4 NFE exome

AF:

0.00230

Gnomad4 OTH exome

AF:

0.00194

GnomAD4 genome

AF:

0.00136

AC:

207

AN:

152358

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000577

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00113

Gnomad4 NFE

AF:

0.00198

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00203

Hom.:

Bravo

AF:

0.00142

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, no assertion criteria provided	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Dec 01, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 22, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 18, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 25, 2018	- -

PTEN hamartoma tumor syndrome

Benign:2

Benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Sep 14, 2016	PTEN c.79+35C>T (IVS1+35C>T) meets criteria to be classified as benign for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). BS1: Allele frequency of 0.00178 (1.78%, 492/277,200 alleles) in the gnomAD cohort. (PMID 27535533) BS3: Intronic variant with RNA, mini-gene, or other splicing assay demonstrating no splicing impact. (PMID 17636424) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 03, 2023	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2024

PTEN: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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