rs878853940

Positions:

• chr10-87864521-GA-G

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.53del​(p.Glu18GlyfsTer6) 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. E18E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTEN NM_000314.8 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.34

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 located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 818 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87864521-GA-G is Pathogenic according to our data. Variant chr10-87864521-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 237648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.53del	p.Glu18GlyfsTer6	frameshift_variant	1/9	ENST00000371953.8
PTEN	NM_001304717.5	c.572del	p.Glu191GlyfsTer6	frameshift_variant	2/10
PTEN	NM_001304718.2	c.-653del		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.53del	p.Glu18GlyfsTer6	frameshift_variant	1/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 26, 2016

For these reasons, this variant has been classified as Pathogenic. Truncating variants in PTEN are known to be pathogenic. This particular truncation has been reported in the literature in an individual affected with Cowden syndrome (PMID: 14566704). This sequence change deletes 1 nucleotide from exon 1 of the PTEN mRNA (c.53delA), causing a frameshift at codon 18. This creates a premature translational stop signal (p.Glu18Glyfs*6) and is expected to result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2015

The c.53delA pathogenic mutation, located in coding exon 1 of the PTEN gene, results from a deletion of one nucleotide at nucleotide position 53, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in an individual with Lhermitte-Duclos disease (Zhao et al. Am. J. Hum. Genet. 2003; 73:1191-8). Different alterations, c.40delA and c.43delA, resulting in a stop codon at the same position (amino acid 23), have also been reported in individuals affected with PTEN-hamartoma tumor syndrome (Toelle et al. Neuropediatrics. 2012; 221-4; Marchese et al. Am. J. Med. Genet. 2003; 120: 286-8). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs878853940; hg19: chr10-89624278;