10-87933228-G-T

Position:

• chr10-87933228-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PVS1 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: PTEN c.469G>T (p.E157X) 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).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 8071972) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000467/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 9.53

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.469G>T	p.Glu157Ter	stop_gained	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.988G>T	p.Glu330Ter	stop_gained	6/10
PTEN	NM_001304718.2	c.-282G>T		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.469G>T	p.Glu157Ter	stop_gained	5/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Cowden syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 28, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Lhermitte-Duclos disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1997

- -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

Clingen PTEN Variant Curation Expert Panel, Clingen

Oct 30, 2018

PTEN c.469G>T (p.E157X) 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). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5' to c.1121 (NM_000314.4). PM2: Absent in large sequenced populations (PMID 27535533). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 8071972) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2021

The p.E157* pathogenic mutation (also known as c.469G>T), located in coding exon 5 of the PTEN gene, results from a G to T substitution at nucleotide position 469. This changes the amino acid from a glutamic acid to a stop codon within coding exon 5. This alteration has been reported in individuals with personal history consistent with PTEN hamartoma tumor syndrome (PHTS)(Eng C et al. J Med Genet, 1994 Jun;31:458-61; Nelen MR et al. Hum Mol Genet, 1997 Aug;6:1383-7; Liaw D et al. Nat Genet, 1997 May;16:64-7; Eng C. Hum Mutat, 2003 Sep;22:183-98; Isik E et al. Ann Hum Genet, 2020 07;84:324-330). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	53
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
Vest4		0.97
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.75		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909220; hg19: chr10-89692985; COSMIC: COSV64290058;