rs587782187

chr10-87864517-T-Achr10-87864517-T-Cchr10-87864517-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>A(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:4
• 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-A is Pathogenic according to our data. Variant chr10-87864517-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 142027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87864517-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.48T>A	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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:1

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. -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 28, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 142027). This premature translational stop signal has been observed in individual(s) with Cowden-like syndrome or breast cancer (PMID: 21194675, 28724667). 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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2019

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28152038, 16773562, 9499454, 10923032, 14566704, 27659017, 24483290, 21194675, 28724667) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2018

The p.Y16* pathogenic mutation (also known as c.48T>A), located in coding exon 1 of the PTEN gene, results from a T to A substitution at nucleotide position 48. This changes the amino acid from a tyrosine to a stop codon within coding exon 1. This alteration has been reported in individuals meeting relaxed International Cowden Consortium operational criteria for Cowden syndrome (Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56). In addition to the clinical data reported in the literature, 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	0.65	D
MutationTaster	Benign	1.0	A
Vest4		0.79
GERP RS		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: COSV64293151; COSMIC: COSV64293151;