10-87961075-CAAAT-CAAATAAAT

Variant names:

• chr10-87961075-C-CAAAT
• rs587782304
• NM_000314.8:c.987_990dupTAAA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000314.8(PTEN):​c.987_990dupTAAA​(p.Asp331fs) variant causes a frameshift, stop gained 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 (i.e. D331D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTEN NM_000314.8 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.15
• Publications: 0 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 12 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 59 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87961075-C-CAAAT is Pathogenic according to our data. Variant chr10-87961075-C-CAAAT is described in CliVar as Pathogenic. Clinvar id is 2673928.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-87961075-C-CAAAT is described in CliVar as Pathogenic. Clinvar id is 2673928.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-87961075-C-CAAAT is described in CliVar as Pathogenic. Clinvar id is 2673928.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-87961075-C-CAAAT is described in CliVar as Pathogenic. Clinvar id is 2673928.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-87961075-C-CAAAT is described in CliVar as Pathogenic. Clinvar id is 2673928.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-87961075-C-CAAAT is described in CliVar as Pathogenic. Clinvar id is 2673928.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-87961075-C-CAAAT is described in CliVar as Pathogenic. Clinvar id is 2673928.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-87961075-C-CAAAT is described in CliVar as Pathogenic. Clinvar id is 2673928.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-87961075-C-CAAAT is described in CliVar as Pathogenic. Clinvar id is 2673928.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-87961075-C-CAAAT is described in CliVar as Pathogenic. Clinvar id is 2673928.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.987_990dupTAAA	p.Asp331fs	frameshift_variant, stop_gained	Exon 8 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1506_1509dupTAAA	p.Asp504fs	frameshift_variant, stop_gained	Exon 9 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.396_399dupTAAA	p.Asp134fs	frameshift_variant, stop_gained	Exon 8 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.987_990dupTAAA	p.Asp331fs	frameshift_variant, stop_gained	Exon 8 of 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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cowden syndrome 1 Pathogenic:1

Oct 09, 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 termination codon and is predicted to result in premature protein truncation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587782304; hg19: chr10-89720832;