10-87933245-CA-C

Position:

• chr10-87933245-CA-C

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.491del​(p.Lys164ArgfsTer3) 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 (★★). 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:7
• Conservation: PhyloP100: 8.88

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 10-87933245-CA-C is Pathogenic according to our data. Variant chr10-87933245-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 189448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87933245-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.491del	p.Lys164ArgfsTer3	frameshift_variant	5/9	ENST00000371953.8
PTEN	NM_001304717.5	c.1010del	p.Lys337ArgfsTer3	frameshift_variant	6/10
PTEN	NM_001304718.2	c.-260del		5_prime_UTR_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.491del	p.Lys164ArgfsTer3	frameshift_variant	5/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 28, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	May 27, 2021	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 29, 2021	The c.491delA pathogenic mutation, located in coding exon 5 of the PTEN gene, results from a deletion of one nucleotide at nucleotide position 491, causing a translational frameshift with a predicted alternate stop codon (p.K164Rfs*3). This mutation has been identified in multiple individuals/families with Cowden syndrome (Bussaglia E et al. J. Invest. Dermatol. 2002 Apr;118:639-44; Caux F et al. Eur. J. Hum. Genet. 2007 Jul;15:767-73; Ngeow J et al. J. Clin. Endocrinol. Metab. 2011 Dec;96:E2063-71; Smith JR et al. J. Clin. Endocrinol. Metab. 2011 Jan;96:34-7; Heindl M et al. Gastroenterology. 2012 May;142:1093-1096.e6; Ngeow J et al. J. Clin. Oncol. 2014 Jun;32:1818-24; Meric-Bernstam F et al. Ann. Oncol. 2016 May;27:795-800; Chen HH et al. J. Allergy Clin. Immunol. 2017 Feb;139:607-620.e15). Of note, this alteration is also designated as c.487del in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2013	This variant is denoted c.491delA at the cDNA level and p.K164RfsX3 at the protein level. Using capital letters to denote exonic sequence and lower case letters to denote intronic sequence, the reference sequence with the base that is deleted in braces is: CAAAA{A}Ggtaag. The c.491delA mutation in the PTEN gene has been reported previously in association with Cowden syndrome, Cowden-like syndrome, and PTEN hamartoma tumor syndrome (Bussaglia et al., 2002; Heindl et at., 2012; Ngeow et al., 2011). Ngeow et al. reported that the c.491delA mutation was present in a patient diagnosed with Cowden/Cowden-like syndrome and thyroid cancer. The deletion causes a frameshift starting with codon Lysine 164, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Lys164ArgfsX3. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is found in PTEN panel(s). -

PTEN hamartoma tumor syndromes Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Oct 12, 2018

This c.491del (p.Lys164Argfs*3) frameshift variant in the PTEN gene is absent from public databases and is predicted to result in the loss of function of PTEN. This variant has been observed in multiple unrelated individual with Cowden syndrome/ PTEN hamartoma syndromes (PMID 11918710 , 17392703, 20962022, 21956414, 24778394) and has been shown to segregate with Cowden syndrome in one family (PMID 17392703). . Based on the above evidence, this c.491del (p.Lys164Argfs*3) variant in the PTEN gene is classified as pathogenic. -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 30, 2022

This sequence change creates a premature translational stop signal (p.Lys164Argfs*3) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with PTEN hamartoma tumor syndrome and Cowden syndrome (PMID: 11918710, 17392703, 21956414, 22266152, 24345843). ClinVar contains an entry for this variant (Variation ID: 189448). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

-

- -

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: rs786204900; hg19: chr10-89693002;