10-87961054-CAA-CA

Variant names:

• chr10-87961054-CA-C
• rs121913291
• NM_000314.8:c.968delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000314.8(PTEN):​c.968delA​(p.Asn323MetfsTer21) 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 (★★). Synonymous variant affecting the same amino acid position has been classified 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
• Publications: 54 publications found

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 Gene-Disease associations (from GenCC):

• Cowden syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• PTEN hamartoma tumor syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• leiomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• activated PI3K-delta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bannayan-Riley-Ruvalcaba syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lhermitte-Duclos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Proteus-like syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• glioma susceptibility 2

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 653412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000314.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	NM_000314.8	MANE Select	c.968delA	p.Asn323MetfsTer21	frameshift	Exon 8 of 9	NP_000305.3
	PTEN	NM_001304717.5		c.1487delA	p.Asn496MetfsTer21	frameshift	Exon 9 of 10	NP_001291646.4
	PTEN	NM_001304718.2		c.377delA	p.Asn126MetfsTer21	frameshift	Exon 8 of 9	NP_001291647.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTEN	ENST00000371953.8	TSL:1 MANE Select	c.968delA	p.Asn323MetfsTer21	frameshift	Exon 8 of 9	ENSP00000361021.3
	PTEN	ENST00000693560.1		c.1487delA	p.Asn496MetfsTer21	frameshift	Exon 9 of 10	ENSP00000509861.1
	PTEN	ENST00000700029.2		c.1061delA	p.Asn354MetfsTer21	frameshift	Exon 9 of 10	ENSP00000514759.2

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

Oct 03, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 04, 2023

Department Of Pathology & Laboratory Medicine, University Of Pennsylvania

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Post-initial therapy specimen.

PTEN hamartoma tumor syndrome Pathogenic:1

Jan 07, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in an individual with clinical features of Cowden syndrome (PMID: 20600018). 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 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

Mar 12, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.99
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913291; hg19: chr10-89720811; COSMIC: COSV64288803;