10-87864517-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000314.8(PTEN):c.48T>G(p.Tyr16Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y16Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTEN NM_000314.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.684

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 818 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87864517-T-G is Pathogenic according to our data. Variant chr10-87864517-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 536556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.48T>G	p.Tyr16Ter	stop_gained	1/9	ENST00000371953.8
PTEN	NM_001304717.5	c.567T>G	p.Tyr189Ter	stop_gained	2/10
PTEN	NM_001304718.2	c.-658T>G		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.48T>G	p.Tyr16Ter	stop_gained	1/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Oct 19, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 21, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 536556). A different variant (c.48T>A) giving rise to the same protein effect has been determined to be pathogenic (PMID: 16773562, 21194675). This suggests that this variant is also likely to be causative of disease. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr16*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	The p.Tyr16X variant in PTEN has been reported as a consequence of at least 4 different cDNA changes and is present in ClinVar (c.48T>G, c.48T>A: ID# 142027, c.48_49delinsAT, or c.47dupA: ID# 234409). The c.48T>G variant, identified in this individual, has not been previously reported in individuals with PTEN hamartoma tumor syndrome (PHTS), but the available data from the other changes supports pathogenicity: Collectively, the p.Tyr16X variant has been reported in at least 6 individuals with phenotypes consistent PTEN hamartoma tumor syndrome (c.48T>A: 2 individuals with Cowden syndrome (SC) (Tan 2011); c.48_49delinsAT: 1 individual with CS and 1 individual with Bannayan-Riley-Ruvalcaba syndrome (BRRS) (Sarquis 2006); c.47dupA: 1 individual with CS or CS-like syndrome with hyperplastic polyps in the upper gastrointestinal tract (Zbuk 2007, Ngeow 2011, Head 2010); p.Tyr16X (cDNA change unspecified: 1 individual with adult Lhermitte-Duclos disease (LDD) and clinical features of Cowden (Zhou 2003)). All changes leading to the pTyr16X variant are absent from large population studies. This variant represents a premature termination codon at position 16, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PTEN gene is an established disease mechanism in PTEN hamartoma tumor syndrome. In summary, the p.Tyr16X variant meets criteria to be classified as pathogenic for PTEN hamartoma tumor syndrome in an autosomal dominant manner based upon absence from controls, predicted impact on the protein, and presence in affected individuals. ACMG/AMP Criteria applied: PVS1, PM2, PS4_moderate. -

Cowden syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 25, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Feb 12, 2021	- -

Familial meningioma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP4,PP5. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2022

The p.Y16* pathogenic mutation (also known as c.48T>G), located in coding exon 1 of the PTEN gene, results from a T to G substitution at nucleotide position 48. This changes the amino acid from a tyrosine to a stop codon within coding exon 1. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.46	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	36
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.66	D
MutationTaster	Benign	1.0	A
Vest4		0.79
GERP RS		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs587782187; hg19: chr10-89624274; COSMIC: COSV64295030; COSMIC: COSV64295030;