rs786204893

chr10-87961075-CAAAT-C

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.987_990del(p.Asn329LysfsTer14) 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. A328A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PTEN NM_000314.8 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 8.85

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 40 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87961075-CAAAT-C is Pathogenic according to our data. Variant chr10-87961075-CAAAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 189441.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr10-87961075-CAAAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.987_990del	p.Asn329LysfsTer14	frameshift_variant	8/9	ENST00000371953.8
PTEN	NM_001304717.5	c.1506_1509del	p.Asn502LysfsTer14	frameshift_variant	9/10
PTEN	NM_001304718.2	c.396_399del	p.Asn132LysfsTer14	frameshift_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.987_990del	p.Asn329LysfsTer14	frameshift_variant	8/9	1	NM_000314.8	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: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2

Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Oct 18, 2017	PTEN c.987_990delTAAA (p.N329KfsX14) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5' to c.1121 (NM_000314.4). PM2: Absent in large sequenced populations (PMID 27535533). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 10232405) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 09, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the PTEN protein in which other variant(s) (p.Leu345Thrfs*8) have been determined to be pathogenic (PMID: 10468583, 10698513, 10866658, 11035045, 12297295, 24905788, 25336918, 25448482). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 189441). This premature translational stop signal has been observed in individuals with clinical features of PTEN hamartoma tumor syndrome (PMID: 10400993, 26082588, 29282348). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn329Lysfs*14) in the PTEN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acid(s) of the PTEN protein. -

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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2023

Frameshift variant predicted to result in protein truncation, as the last 75 amino acids are replaced with 13 different amino acids, disrupting the critical C2 domain (Wang et al., 2008); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21956414, 10400993, 18626510, 26082588, 35227301, 26205736, 14518068, 12938083, 28152038, 30311380, 29282348, 26612463) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2013

Alterations resulting in premature truncation (e.g.reading frame shift, nonsense) -

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: rs587782304; hg19: chr10-89720832;