rs121913289

chr10-87958012-TA-Tchr10-87958012-TA-TAA

Variant summary

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

The NM_000314.8(PTEN):c.800del(p.Lys267ArgfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L265L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PTEN NM_000314.8 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.45

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 10-87958012-TA-T is Pathogenic according to our data. Variant chr10-87958012-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 92828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.800del	p.Lys267ArgfsTer9	frameshift_variant	7/9	ENST00000371953.8
PTEN	NM_001304717.5	c.1319del	p.Lys440ArgfsTer9	frameshift_variant	8/10
PTEN	NM_001304718.2	c.209del	p.Lys70ArgfsTer9	frameshift_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.800del	p.Lys267ArgfsTer9	frameshift_variant	7/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461634 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2015	The c.800delA variant in the PTEN gene has been report in association with PTEN-related disorders (Lachlan et al., 2007; Ngeow et al., 2011). The c.800delA deletion in the PTEN gene causes a frameshift starting with codon Lysine 267, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 9 of the new reading frame, denoted p.Lys267ArgfsX9. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we interpret c.800delA to be a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -

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. -

Malignant lymphoma, large B-cell, diffuse Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department Of Pathology & Laboratory Medicine, University Of Pennsylvania

Dec 04, 2023

Post-initial therapy specimen. -

Breast neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 11, 2015

This sequence change deletes 1 nucleotide from exon 7 of the PTEN mRNA (c.800delA), causing a frameshift at codon 267. This creates a premature translational stop signal (p.Lys267Argfs*9) and is expected to result in an absent or disrupted protein product. Truncating variants in PTEN are known to be pathogenic. This particular truncation has been reported in patients affected with Bannayan-Riley-Ruvalcaba syndrome (PMID: 17526800), thyroid cancer (PMID: 21956414), and endometrial carcinoma (PMID: 23949151). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2018

The c.800delA pathogenic mutation, located in coding exon 7 of the PTEN gene, results from a deletion of one nucleotide at nucleotide position 800, causing a translational frameshift with a predicted alternate stop codon (p.K267Rfs*9). This mutation has been reported in an individual meeting clinical diagnostic criteria for Cowden syndrome (Lachlan KL et al. J. Med. Genet. 2007 Sep;44:579-85), as well as in individuals meeting relaxed International Cowden Consortium operational criteria for Cowden syndrome (Tan MH et al. Am. J. Hum. Genet. 2011 Jan;88(1):42-56). 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. -

Neoplasm of the large intestine Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

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: rs121913289; hg19: chr10-89717769;