10-87932974-GTTTT-GTTTTT

Position:

• chr10-87932974-GTTTT-GTTTTT

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.254-30dup (IVS4-30dup) meets criteria to be classified as benign 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).BA1: Allele frequency of 0.01437 (1.437%, 3748/260,738 alleles) in the gnomAD cohort. (PMID 27535533) LINK:https://erepo.genome.network/evrepo/ui/classification/CA146028/MONDO:0017623/003

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 32)
  • Exomes 𝑓: 0.014 (112 hom.)
• Consequence: PTEN NM_000314.8 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:5
• Conservation: PhyloP100: 1.19

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 (HGNC:):

ACMG classification

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	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.254-30dupT		intron_variant		ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.773-30dupT		intron_variant			NP_001291646.4
PTEN	NM_001304718.2	c.-497-30dupT		intron_variant			NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.254-30dupT		intron_variant		1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1571 AN: 151410 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00994

Gnomad ASJ AF: 0.0344

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0139

Gnomad OTH AF: 0.0155

GnomAD3 exomes AF: 0.0147 AC: 3371 AN: 229604 Hom.: 33 AF XY: 0.0159 AC XY: 1981 AN XY: 124852

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.0385

Gnomad EAS exome AF: 0.000118

Gnomad SAS exome AF: 0.0177

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0180

GnomAD4 exome AF: 0.0137 AC: 17934 AN: 1311240 Hom.: 112 Cov.: 23 AF XY: 0.0140 AC XY: 9255 AN XY: 659250

Gnomad4 AFR exome AF: 0.00315

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.0350

Gnomad4 EAS exome AF: 0.000494

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0104 AC: 1570 AN: 151528 Hom.: 19 Cov.: 32 AF XY: 0.00997 AC XY: 739 AN XY: 74088

Gnomad4 AFR AF: 0.00191

Gnomad4 AMR AF: 0.00993

Gnomad4 ASJ AF: 0.0344

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0140

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.0139

Gnomad4 OTH AF: 0.0148

Bravo AF: 0.00991

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Cowden syndrome 1 Uncertain:1

Uncertain significance, no assertion criteria provided

research

Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute

May 26, 2017

- -

PTEN hamartoma tumor syndrome Benign:1

Benign, reviewed by expert panel

curation

Clingen PTEN Variant Curation Expert Panel, Clingen

Nov 22, 2019

PTEN c.254-30dup (IVS4-30dup) meets criteria to be classified as benign 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). BA1: Allele frequency of 0.01437 (1.437%, 3748/260,738 alleles) in the gnomAD cohort. (PMID 27535533) -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 09, 2014

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs77494260; hg19: chr10-89692731;