10-87925543-C-G

Position:

• chr10-87925543-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PS4_Supporting

This summary comes from the ClinGen Evidence Repository: PTEN c.195C>G (p.Y65X) meets criteria to be classified as pathogenic 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).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23335809) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10582757/MONDO:0017623/003

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 1.85

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.195C>G	p.Tyr65*	stop_gained	3/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.714C>G	p.Tyr238*	stop_gained	4/10		NP_001291646.4
PTEN	NM_001304718.2	c.-541-5503C>G		intron_variant			NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.195C>G	p.Tyr65*	stop_gained	3/9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

PTEN hamartoma tumor syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 16, 2021	For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with Cowden syndrome (PMID: 21194675, 23335809). This sequence change creates a premature translational stop signal (p.Tyr65*) 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). -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Mar 05, 2019	PTEN c.195C>G (p.Y65X) meets criteria to be classified as pathogenic 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). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4). PM2: Absent in large sequenced populations (PMID 27535533). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23335809) -

Cowden syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Sep 26, 2023

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

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The p.Y65* pathogenic mutation (also known as c.195C>G), located in coding exon 3 of the PTEN gene, results from a C to G substitution at nucleotide position 195. This changes the amino acid from a tyrosine to a stop codon within coding exon 3. This alteration has been reported in an individual meeting relaxed International Cowden Consortium operational criteria for Cowden syndrome (Tan MH et al. Am J Hum Genet, 2011 Jan;88:42-56). 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 May;102:943-955). This variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.89
GERP RS		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs878853936; hg19: chr10-89685300; COSMIC: COSV64293906;