rs1064792910

Positions:

• chr10-87933104-T-TGACAATCATGTTG

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.346_358dup​(p.Ala120GlyfsTer10) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.53

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87933104-T-TGACAATCATGTTG is Pathogenic according to our data. Variant chr10-87933104-T-TGACAATCATGTTG is described in ClinVar as [Pathogenic]. Clinvar id is 404150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.346_358dup	p.Ala120GlyfsTer10	frameshift_variant	5/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.865_877dup	p.Ala293GlyfsTer10	frameshift_variant	6/10		NP_001291646.4
PTEN	NM_001304718.2	c.-405_-393dup		5_prime_UTR_variant	4/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.346_358dup	p.Ala120GlyfsTer10	frameshift_variant	5/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 20, 2016

This sequence change inserts 13 nucleotides in exon 5 of the PTEN mRNA (c.346_358dupGACAATCATGTTG), causing a frameshift at codon 120. This creates a premature translational stop signal (p.Ala120Glyfs*10) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with  PTEN hamartoma tumor syndrome (PMID: 17526801). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 22, 2022

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported in an individual with features of PTEN hamartoma tumor syndrome, who is likely this same patient (Tan et al., 2007); This variant is associated with the following publications: (PMID: 17526801) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064792910; hg19: chr10-89692861;