10-87925551-A-G

Position:

• chr10-87925551-A-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.203A>G​(p.Tyr68Cys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y68?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.65

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 strand (size 8) in uniprot entity PTEN_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr10-87925550-TAC-TT is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTEN. . Gene score misZ 3.4883 (greater than the threshold 3.09). Trascript score misZ 4.1129 (greater than threshold 3.09). GenCC has associacion of gene with Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, macrocephaly-autism syndrome, Cowden syndrome 1, Cowden disease, Proteus-like syndrome, leiomyosarcoma, activated PI3K-delta syndrome, PTEN hamartoma tumor syndrome, glioma susceptibility 2, renal cell carcinoma.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 10-87925551-A-G is Pathogenic according to our data. Variant chr10-87925551-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 233777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87925551-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8	c.203A>G	p.Tyr68Cys	missense_variant	3/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.722A>G	p.Tyr241Cys	missense_variant	4/10		NP_001291646.4
PTEN	NM_001304718.2	c.-540-5495A>G		intron_variant			NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.203A>G	p.Tyr68Cys	missense_variant	3/9	1	NM_000314.8	ENSP00000361021	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cowden syndrome 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 26, 2023	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29785012, Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19457929, 26246517, 29296277, 32003824]. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 26, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Apr 11, 2023	- -

Autism;C0036572:Seizure;C0338656:Cognitive impairment;C0557874:Global developmental delay;C1836830:Developmental regression;C3887898:Infantile spasms;C4048268:Cerebral visual impairment;C4551563:Microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

-

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 68 of the PTEN protein (p.Tyr68Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cowden syndrome (PMID: 19457929, 21956414, 24778394, 26246517). ClinVar contains an entry for this variant (Variation ID: 233777). 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. Experimental studies have shown that this missense change affects PTEN function (PMID: 19457929, 26246517). This variant disrupts the p.Tyr68 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9600246, 16704655, 19457929, 20926450, 25669429). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 05, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: aberrant phosphatase activity and cellular localization (PMID: 19457929, 29706350); Identified in additional patients with PTEN-related phenotypes referred for genetic testing at GeneDx and in published literature (PMID: 26246517, 24778394); Identified as a de novo variant with confirmed parentage in a patient previously tested at GeneDx and as an apparently de novo variant in multiple patients previously tested at GeneDx and in the published literature with features of PTEN Hamartoma Tumor syndrome (PMID: 29296277); This variant is associated with the following publications: (PMID: 24778394, 26246517, 29785012, 21956414, 19457929, 30287823, 9288766, 25669429, 29296277, 32003824, 30755392, 31594918, 29706350, 24475377) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2021

The p.Y68C pathogenic mutation (also known as c.203A>G), located in coding exon 3 of the PTEN gene, results from an A to G substitution at nucleotide position 203. The tyrosine at codon 68 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in numerous individuals with a personal history of Cowden syndrome or Cowden-like disease (Ngeow J, J. et al. Clin. Endocrinol. Metab. 2011 Dec;96(12):E2063-71; Ngeow J et al. J. Clin. Oncol. 2014 Jun;32(17):1818-24; Browning MJ et al. J. Med. Genet. 2015 Aug). Functional analyses in isolated T cells from one affected individual showed reduced PTEN protein expression and increased AKT and S6 phosphorylation in peripheral blood T cells (Browning MJ et al. J. Med. Genet. 2015 Aug). This alteration has also been shown to disrupt function using a humanized yeast model of lipid phosphatase activity in vivo (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955), and demonstrated low intracellular protein abundance on a multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882). In addition, this alteration is located in a putative ATP-biding site, and is associated with an increase in PTEN nuclear localization compared to wildtype controls (Lobo GP et al. Hum. Mol. Genet. 2009 Aug;18(15):2851-62). Further, similar alterations at this codon (p.Y68H, p.Y68S, p.Y68D) have also been reported in individuals with PTEN hamartoma tumor syndrome (PHTS), including a boy with a clinical diagnosis of proteus syndrome and his mother with clinical features of Cowden syndrome (Ambry Internal data, Loffeld A et al. Br. J. Dermatol. 2006;154 (6):1194-8). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.7	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.86		Gain of sheet (P = 0.0344);
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs876660634; hg19: chr10-89685308; COSMIC: COSV64293993;