rs1060500115

Positions:

• chr10-87957938-CT-C
• chr10-87957938-CT-CTT
• chr10-87957938-CT-CTTT

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.723del​(p.Phe241LeufsTer15) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. F241F) has been classified as Benign. 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:3
• Conservation: PhyloP100: 7.62

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 10-87957938-CT-C is Pathogenic according to our data. Variant chr10-87957938-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 667418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87957938-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.723del	p.Phe241LeufsTer15	frameshift_variant	7/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.1242del	p.Phe414LeufsTer15	frameshift_variant	8/10		NP_001291646.4
PTEN	NM_001304718.2	c.132del	p.Phe44LeufsTer15	frameshift_variant	7/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.723del	p.Phe241LeufsTer15	frameshift_variant	7/9	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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Breda Genetics srl

Jul 31, 2020

The variant c.723del (p.Phe241Leufs*15) in the PTEN gene is reported as pathogenic for PTEN hamartoma tumor syndrome in ClinVar (Variation ID: 667418). The variant creates a shift in the reading frame which is predicted to result in a premature stop codon 15 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). This variant has not been reported in dbSNP, gnomAD, 1000 Genomes, NHLI Exome Sequencing Project (ESP). This pathogenic variant has already been reported by Henderson et al. (2014) in a pediatric case of PTEN hamartoma tumor syndromes (PMID: 24345843). Moreover, the variant falls in a region rich in pathogenic frameshift mutation in Clinvar. -

Cowden syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Sep 29, 2023

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 27, 2018

The p.Phe241fs variant in PTEN has been reported in one individual with PTEN-ham artoma tumor syndrome (PHTS) and eosinophilic gastrointestinal disorders (Hender son 2014), and was absent from large population studies. This variant is predict ed to cause a frameshift, which alters the protein?s amino acid sequence beginni ng at position 241 and leads to a premature termination codon 15 amino acids dow nstream. This alteration is then predicted to lead to a truncated or absent prot ein. Heterozygous loss of function of the PTEN gene is an established disease me chanism in PHTS. Additionally, two other variants at this position have been rep orted in individuals with macrocephaly and PTEN-related tumors (Marsh 1998, Buis son 2006). In summary, this variant meets criteria to be classified as pathogeni c for PHTS in an autosomal dominant manner based upon the predicted impact on th e protein. ACMG/AMP Criteria applied: PVS1, PMS2, PS4_Supporting. -

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: rs1060500115; hg19: chr10-89717695;