rs1114167625

chr10-87864507-AAAG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4_Supporting PP5_Strong

The NM_000314.8(PTEN):c.39_41del(p.Arg15del) variant causes a inframe deletion 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 Uncertain significance (★★★). 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 inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 8.95

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000314.8. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 10-87864507-AAAG-A is Pathogenic according to our data. Variant chr10-87864507-AAAG-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 428199.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.39_41del	p.Arg15del	inframe_deletion	1/9	ENST00000371953.8
PTEN	NM_001304717.5	c.558_560del	p.Arg188del	inframe_deletion	2/10
PTEN	NM_001304718.2	c.-667_-665del		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.39_41del	p.Arg15del	inframe_deletion	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: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 14, 2023	This variant, c.39_41del, results in the deletion of 1 amino acid(s) of the PTEN protein (p.Arg15del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Cowden syndrome (PMID: 25669429, 30528446). ClinVar contains an entry for this variant (Variation ID: 428199). This variant disrupts a region of the PTEN protein in which other variant(s) (p.Arg15Ser) have been determined to be pathogenic (PMID: 16773562, 17942903, 21417916, 21659347, 25875300, 29706350; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Jun 04, 2021	PTEN c.39_41del (p.Arg15del) is currently classified as a variant of uncertain significance for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PM2: Absent in large sequenced populations (PMID 27535533). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 30528446) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2013

​The c.39_41delAAG variant is located in coding exon 1 of the PTEN gene. This variant results from an in-frame 3 base pair deletion between nucleotide positions 39 and 41.This results in the deletion of the arginine residue at codon 14.This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 14,000 alleles tested) in our clinical cohort (includes this individual). Based on sequence alignment,these nucleotide positions andthis amino acid position are highly conserved in available vertebrate species.An in-frame deletion of the adjacent arginine at codon 15 has been reportedin an individual meeting relaxed CS operational criteria (pathognomonic criteria, or at least two major or minor criteria) (Tan, MH et al. Am J Hum Genet. 2011 Jan 7;88(1):42-56). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1114167625; hg19: chr10-89624264;