rs398123330

Positions:

• chr10-87961047-ACTTT-A

Variant summary

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

The ENST00000371953.8(PTEN):​c.956_959del​(p.Thr319LysfsTer24) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T319T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTEN ENST00000371953.8 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.57

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87961047-ACTTT-A is Pathogenic according to our data. Variant chr10-87961047-ACTTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 92836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87961047-ACTTT-A is described in Lovd as [Likely_pathogenic]. Variant chr10-87961047-ACTTT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.956_959del	p.Thr319LysfsTer24	frameshift_variant	8/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1475_1478del	p.Thr492LysfsTer24	frameshift_variant	9/10		NP_001291646.4
PTEN	NM_001304718.2	c.365_368del	p.Thr122LysfsTer24	frameshift_variant	8/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.956_959del	p.Thr319LysfsTer24	frameshift_variant	8/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2022	Reported in an individual with personal history suspicious for PTEN Hamartoma Tumor syndrome (Tan et al., 2007); Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24905788, 24307375, 21194675, 31062505, 10698513, 10468583) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2013	- -

Cowden syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Oct 02, 2023

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 02, 2020

This sequence change results in a premature translational stop signal in the PTEN gene (p.Thr319Lysfs*24). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 85 amino acids of the PTEN protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Cowden or Cowden-like syndrome (PMID: 21194675). ClinVar contains an entry for this variant (Variation ID: 92836). This variant disrupts the C-terminus of the PTEN protein. Other variant(s) that disrupt this region (p.Ala333Serfs*10) have been determined to be pathogenic (PMID: 10468583, 10698513, 24905788, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2020

The c.956_959delCTTT pathogenic mutation, located in coding exon 8 of the PTEN gene, results from a deletion of 4 nucleotides at positions 956 to 959, causing a translational frameshift with a predicted alternate stop codon (p.T319Kfs*24). This mutation has been reported in a patient meeting relaxed International Cowden Consortium operational criteria for Cowden Syndrome at age 40 (Tan et al. Am J Hum Genet. 2011 Jan 7;88(1):42-56). 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. -

Computational scores

Source: dbNSFP v4.3

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: rs398123330; hg19: chr10-89720804; COSMIC: COSV64288731;