rs1554893765

Positions:

• chr10-87894038-CATT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP1 PS3_Moderate PM6_Strong PM2_Supporting

This summary comes from the ClinGen Evidence Repository: PTEN c.97_99delATT (c.94ATT[1]) (p.Ile33del) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3_Moderate: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID:29706350.PM2_Supporting: Absent in large sequenced populations (PMID 27535533).PM6_Strong: An individual with a highly specific phenotype (Internal laboratory contributor SCV000616838.1).PP1: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (PMID 10234502 , internal laboratory contributor SCV002559099.1) LINK:https://erepo.genome.network/evrepo/ui/classification/CV449088/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 7.54

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]

PTEN (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: 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.97_99delATT	p.Ile33del	conservative_inframe_deletion	2/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.616_618delATT	p.Ile206del	conservative_inframe_deletion	3/10		NP_001291646.4
PTEN	NM_001304718.2	c.-609_-607delATT		5_prime_UTR_variant	2/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.97_99delATT	p.Ile33del	conservative_inframe_deletion	2/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This variant, c.97_99del, results in the deletion of 1 amino acid(s) of the PTEN protein (p.Ile33del), 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 features of Bannayan-Riley-Ruvalcaba syndrome or adult-onset Lhermitte-Duclos disease and Cowden syndrome (PMID: 10234502; Invitae; external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 449088). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Aug 04, 2023	PTEN c.97_99delATT (c.94ATT[1]) (p.Ile33del) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_Moderate: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350. PM2_Supporting: Absent in large sequenced populations (PMID 27535533). PM6_Strong: An individual with a highly specific phenotype (Internal laboratory contributor SCV000616838.1). PP1: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (PMID 10234502 , internal laboratory contributor SCV002559099.1) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2022	In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect: significantly reduced lipid phosphatase activity in a high-throughput assay (Mighell 2018); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21194675, 18558293, 10923032, 23674493, 9765621, 30325992, 33163849, 31594918, 10234502, 29706350, 24475377) -

Neurodevelopmental delay Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

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Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.97_99delATT variant (also known as p.I33del) is located in coding exon 2 of the PTEN gene. This variant results from an in-frame ATT deletion at nucleotide positions 97 to 99. This results in the in-frame deletion of an isoleucine at codon 33. This alteration has been reported in multiple individuals with PTEN hamartoma tumor syndrome (Ambry internal data; Nelen MR et al. Eur. J. Hum. Genet., 1999 Apr;7:267-73; Busch RM et al. Transl Psychiatry, 2019 10;9:253). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Lee CU et al. Angew Chem Int Ed Engl, 2015 Nov;54:13796-800). The deleted amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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)		0.27		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.27		Position offset: -20

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554893765; hg19: chr10-89653795;