rs587776671

chr10-87864505-CAA-Cchr10-87864505-CAA-CAAAchr10-87864505-CAA-CAAAA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000314.8(PTEN):c.39_40del(p.Arg14GlufsTer29) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K13K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTEN NM_000314.8 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 16 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 837 pathogenic variants in the truncated region.
• PP5: Variant 10-87864505-CAA-C is Pathogenic according to our data. Variant chr10-87864505-CAA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 450810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87864505-CAA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.39_40del	p.Arg14GlufsTer29	frameshift_variant	1/9	ENST00000371953.8
PTEN	NM_001304717.5	c.558_559del	p.Arg187GlufsTer29	frameshift_variant	2/10
PTEN	NM_001304718.2	c.-667_-666del		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.39_40del	p.Arg14GlufsTer29	frameshift_variant	1/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2018	The c.39_40delAA variant in the PTEN gene has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant (Wei et al., 2015; Wong et al., 2015). This deletion causes a frameshift which changes an Arginine to a Glutamic Acid at codon 14, and creates a premature stop codon at position 29 of the new reading frame, denoted p.Arg14GlufsX29. This variant is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The c.39_40delAA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Based on currently available evidence, we consider c.39_40delAA to be pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Cowden syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Dec 22, 2022

ACMG classification criteria: PVS1 strong, PS4 supporting, PM2 moderated -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 14, 2022

The c.39_40delAA pathogenic mutation, located in coding exon 1 of the PTEN gene, results from a deletion of two nucleotides at nucleotide positions 39 to 40, causing a translational frameshift with a predicted alternate stop codon (p.R14Efs*29). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with PTEN hamartoma tumor syndrome (Pena-Couso L et al. Orphanet J Rare Dis, 2022 02;17:85). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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: rs587776671; hg19: chr10-89624262;