10-87961054-CAA-CA

Position:

• chr10-87961054-CAA-CA

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.968delA​(p.Asn323fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTEN NM_000314.8 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.995

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]

PTEN (HGNC:):

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 10-87961054-CA-C is Pathogenic according to our data. Variant chr10-87961054-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 653412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.968delA	p.Asn323fs	frameshift_variant	8/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1487delA	p.Asn496fs	frameshift_variant	9/10		NP_001291646.4
PTEN	NM_001304718.2	c.377delA	p.Asn126fs	frameshift_variant	8/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.968delA	p.Asn323fs	frameshift_variant	8/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

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.

Oct 03, 2023

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

Malignant lymphoma, large B-cell, diffuse Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department Of Pathology & Laboratory Medicine, University Of Pennsylvania

Dec 04, 2023

Post-initial therapy specimen. -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2020

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 81 amino acids (Ala323-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 an individual with clinical features of Cowden syndrome (PMID: 20600018). 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.Asn323Metfs*21). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 amino acids of the PTEN protein. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2018

The c.968delA pathogenic mutation, located in coding exon 8 of the PTEN gene, results from a deletion of one nucleotide at nucleotide position 968, causing a translational frameshift with a predicted alternate stop codon (p.N323Mfs*21). This alteration has been reported in two separate studies evaluating probands meeting relaxed International Cowden Consortium PHTS criteria (Heald B et al. Gastroenterology 2010 Dec;139(6):1927-33; Nizialke EA et al. Eur. J. Hum. Genet. 2015 Nov;23(11):1538-43). This mutation, designated as 967delA, was also detected in a mosaic state in an individual who presented with multiple colonic ganglioneuromas, tongue papules, macrocephaly, thyroid goiter, and suspected trichilemmoma (Gammon A et al. Clin. Genet. 2013 Dec;84(6):593-5). 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

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: rs121913291; hg19: chr10-89720811;