10-87894049-T-G

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000314.8(PTEN):c.104T>G(p.Met35Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M35I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.53

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 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000314.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-87894050-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 536558.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 10-87894049-T-G is Pathogenic according to our data. Variant chr10-87894049-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 7825.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.104T>G	p.Met35Arg	missense_variant	2/9	ENST00000371953.8
PTEN	NM_001304717.5	c.623T>G	p.Met208Arg	missense_variant	3/10
PTEN	NM_001304718.2	c.-602T>G		5_prime_UTR_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.104T>G	p.Met35Arg	missense_variant	2/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Cowden syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2003	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 06, 2023	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29785012]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 37819013, 9425889]. -

PTEN hamartoma tumor syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 35 of the PTEN protein (p.Met35Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 9425889). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7825). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 21828076, 25875300). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Met35 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 17526801, 26468640; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Jul 25, 2018	PTEN c.104T>G (p.Met35Arg) 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (PMID 9425889) PS3: Phosphatase activity <50% of wild type. (PMID 21828076, 25875300) PM2: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	34
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.97		Loss of sheet (P = 0.0315);
MVP		1.0
MPC		4.9
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909225; hg19: chr10-89653806; COSMIC: COSV64292490;