rs555895

Positions:

chr10-87961150-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: PTEN c.1026+32T>G (IVS8+32T>G) 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).BA1: Allele frequency of 0.374 (37.4%, 102,771/274,696 alleles) in the gnomAD cohort. (PMID 27535533) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000255/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.40 ( 12672 hom., cov: 31)

Exomes 𝑓: 0.36 ( 93105 hom. )

Consequence

PTEN
NM_000314.8 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: -0.850

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 Benign. Variant got -8 ACMG points.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
PTEN	NM_000314.8 linkuse as main transcript	c.1026+32T>G	intron_variant	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 linkuse as main transcript	c.1545+32T>G	intron_variant		NP_001291646.4
PTEN	NM_001304718.2 linkuse as main transcript	c.436+32T>G	intron_variant		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.1026+32T>G		intron_variant		1	NM_000314.8	ENSP00000361021	P1	P60484-1

Frequencies

GnomAD3 genomes

AF:

0.399

AC:

60661

AN:

151868

Hom.:

12632

Cov.:

show subpopulations

Gnomad AFR

AF:

0.501

Gnomad AMI

AF:

0.273

Gnomad AMR

AF:

0.451

Gnomad ASJ

AF:

0.377

Gnomad EAS

AF:

0.506

Gnomad SAS

AF:

0.300

Gnomad FIN

AF:

0.344

Gnomad MID

AF:

0.443

Gnomad NFE

AF:

0.336

Gnomad OTH

AF:

0.407

GnomAD3 exomes

AF:

0.373

AC:

92706

AN:

248338

Hom.:

17918

AF XY:

0.363

AC XY:

48929

AN XY:

134850

show subpopulations

Gnomad AFR exome

AF:

0.498

Gnomad AMR exome

AF:

0.457

Gnomad ASJ exome

AF:

0.371

Gnomad EAS exome

AF:

0.489

Gnomad SAS exome

AF:

0.309

Gnomad FIN exome

AF:

0.344

Gnomad NFE exome

AF:

0.335

Gnomad OTH exome

AF:

0.371

GnomAD4 exome

AF:

0.358

AC:

511154

AN:

1426510

Hom.:

93105

Cov.:

AF XY:

0.355

AC XY:

252501

AN XY:

711724

show subpopulations

Gnomad4 AFR exome

AF:

0.508

Gnomad4 AMR exome

AF:

0.462

Gnomad4 ASJ exome

AF:

0.370

Gnomad4 EAS exome

AF:

0.500

Gnomad4 SAS exome

AF:

0.307

Gnomad4 FIN exome

AF:

0.342

Gnomad4 NFE exome

AF:

0.348

Gnomad4 OTH exome

AF:

0.375

GnomAD4 genome

AF:

0.400

AC:

60753

AN:

151986

Hom.:

12672

Cov.:

AF XY:

0.398

AC XY:

29556

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.502

Gnomad4 AMR

AF:

0.452

Gnomad4 ASJ

AF:

0.377

Gnomad4 EAS

AF:

0.506

Gnomad4 SAS

AF:

0.300

Gnomad4 FIN

AF:

0.344

Gnomad4 NFE

AF:

0.336

Gnomad4 OTH

AF:

0.414

Alfa

AF:

0.364

Hom.:

1963

Bravo

AF:

0.413

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30316882) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 70% of patients studied by a panel of primary immunodeficiencies. Number of patients: 62. Only high quality variants are reported. -

Cowden syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -

PTEN hamartoma tumor syndrome

Benign:2

Benign, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Sep 14, 2016	PTEN c.1026+32T>G (IVS8+32T>G) 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). BA1: Allele frequency of 0.374 (37.4%, 102,771/274,696 alleles) in the gnomAD cohort. (PMID 27535533) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Mar 26, 2020

- -

Macrocephaly-autism syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Oct 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.69

DANN

Benign

0.37

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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