rs786201816

Positions:

• chr10-87961100-C-G
• chr10-87961100-C-T

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.1008C>G​(p.Tyr336Ter) 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. Y336Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTEN NM_000314.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.476

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 is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87961100-C-G is Pathogenic according to our data. Variant chr10-87961100-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 481172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87961100-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.1008C>G	p.Tyr336Ter	stop_gained	8/9	ENST00000371953.8
PTEN	NM_001304717.5	c.1527C>G	p.Tyr509Ter	stop_gained	9/10
PTEN	NM_001304718.2	c.417C>G	p.Tyr139Ter	stop_gained	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.1008C>G	p.Tyr336Ter	stop_gained	8/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

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.

Oct 09, 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

Mar 13, 2019

For these reasons, this variant has been classified as Pathogenic. No functional studies have been performed to test the effects of this particular variant on PTEN protein stability, cellular location, or function. However, experimental studies have shown that other C-terminal truncating variants in this region affect the stability and function of the PTEN protein (PMID: 10468583, 10698513, 24905788), suggesting that deletion of this region of the PTEN protein is causative of disease. This variant is expected to result in the disruption of the last 68 amino acids (Tyr336-Val403) of the PTEN protein. This removes the C-terminal portion of the C2 domain, as well as the entire C-tail domain and PDZ binding domain (PMID: 25448482, 25336918, 24905788). This variant also deletes several critical phosphorylation sites within the C-tail domain, which are important for regulating PTEN protein stability and function (PMID: 12297295, 10866658, 11035045, 10468583). This variant has been observed in several individuals affected with PTEN-related disease (PMID: 20223021, 27477328, 28086757). This variant is also known as c.1006C>G and p.Tyr337X in the literature. ClinVar contains an entry for this variant (Variation ID: 481172). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the PTEN gene (p.Tyr336*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 68 amino acids of the PTEN protein. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The p.Y336* variant (also known as c.1008C>G), located in coding exon 8 of the PTEN gene, results from a C to G substitution at nucleotide position 1008. This changes the amino acid from a tyrosine to a stop codon within coding exon 8. This mutation has been reported in several individuals and/or families with clinical manifestations of the PTEN hamartoma tumor syndrome (PHTS) including Cowden or Cowden-like syndrome and Bannayan-Riley-Ruvalcaba syndrome (Rustad CF et al. Hered Cancer Clin Pract. 2006 Dec;4:177-85; Negishi Y et al. BMC Med. Genet. 2017 Jan;18:4; Chen HH et al. J. Allergy Clin. Immunol. 2017 Feb;139:607-620.e15). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. This alteration is also referred to as c.1006C>G in the literature. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.43
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	D
Vest4		0.97
GERP RS		-0.80

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

Other links and lift over

dbSNP: rs786201816; hg19: chr10-89720857; COSMIC: COSV64292408;