rs587780003

Positions:

• chr10-87965309-CAGT-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. BS3_Supporting PM2

This summary comes from the ClinGen Evidence Repository: PTEN c.1052_1054delTAG (p.Val351del) 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). BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000271/MONDO:0017623/003

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel U:6
• Conservation: PhyloP100: 7.59

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.1052_1054del	p.Val351del	inframe_deletion	9/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1571_1573del	p.Val524del	inframe_deletion	10/10		NP_001291646.4
PTEN	NM_001304718.2	c.461_463del	p.Val154del	inframe_deletion	9/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.1052_1054del	p.Val351del	inframe_deletion	9/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.86e-7 AC: 1 AN: 1457386 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 724614

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 05, 2021	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this variant does not substantially affect PTEN protein function (PMID: 29706350). This variant has not been reported in the literature in individuals with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 127687). This variant is not present in population databases (ExAC no frequency). This variant, c.1052_1054del, results in the deletion of 1 amino acid(s) of the PTEN protein (p.Val351del), but otherwise preserves the integrity of the reading frame. -
Uncertain significance, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Mar 23, 2020	PTEN c.1052_1054delTAG (p.Val351del) 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). BS3_P: In vitro or in vivo functional study or studies showing no damaging effect on protein function but BS3 not met. (PMID 29706350) -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2018	This in-frame deletion of three nucleotides in PTEN is denoted c.1052_1054delTAG at the cDNA level and p.Val351del (V351del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ACAG[delTAG]AGGA. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PTEN Val351del was not observed in large population cohorts (Lek 2016). This deletion of a single Valine residue is located in the C2 domain (Wang 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider PTEN Val351del to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	PTEN: PM2, PM4:Supporting -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 06, 2023	The c.1052_1054delTAG variant (also known as p.V351del) is located in coding exon 9 of the PTEN gene. This variant results from an in-frame TAG deletion at nucleotide positions 1052 to 1054. This results in the in-frame deletion of a valine at codon 351. This alteration is classified as a variant of unknown significance by the ClinGen PTEN Expert Panel (Mester JL et al. Hum Mutat, 2018 11;39:1581-1592). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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: rs587780003; hg19: chr10-89725066;