10-87965397-T-G

Variant names:

• chr10-87965397-T-G
• rs1295420243
• NM_000314.8:c.1137T>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000314.8(PTEN):​c.1137T>G​(p.Tyr379*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.217

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0619 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87965397-T-G is Pathogenic according to our data. Variant chr10-87965397-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 818395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.1137T>G	p.Tyr379*	stop_gained	Exon 9 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1656T>G	p.Tyr552*	stop_gained	Exon 10 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.546T>G	p.Tyr182*	stop_gained	Exon 9 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.1137T>G	p.Tyr379*	stop_gained	Exon 9 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Dec 06, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Not found in the total gnomAD dataset, and the data is high quality. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 18, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y379* variant (also known as c.1137T>G), located in coding exon 9 of the PTEN gene, results from a T to G substitution at nucleotide position 1137. This changes the amino acid from a tyrosine to a stop codon within coding exon 9. This stop codon occurs at the 3' terminus of PTEN, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 25 amino acids of the protein. Experimental literature points to this region being crucial for regulation of PTEN activity (Georgescu MM et al. Proc. Natl. Acad. Sci. U.S.A., 1999 Aug;96:10182-7; Hopkins BD et al. Trends Biochem. Sci., 2014 Apr;39:183-90; Sun Z et al. Cell Rep, 2014 Mar;6:844-54; Vazquez F et al. Mol. Cell. Biol., 2000 Jul;20:5010-8). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.84	D
Vest4		0.81
GERP RS		2.9

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: rs1295420243; hg19: chr10-89725154;