10-87925550-T-C

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.202T>C(p.Tyr68His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,424,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. Y68N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 7.42

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 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 chr10-87925551-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.
• PP2: Missense variant where missense usually causes diseases, PTEN
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 10-87925550-T-C is Pathogenic according to our data. Variant chr10-87925550-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87925550-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTEN	NM_000314.8	c.202T>C	p.Tyr68His	missense_variant	3/9	ENST00000371953.8
PTEN	NM_001304717.5	c.721T>C	p.Tyr241His	missense_variant	4/10
PTEN	NM_001304718.2	c.-540-5496T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8	c.202T>C	p.Tyr68His	missense_variant	3/9	1	NM_000314.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1424326 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 709980

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

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. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9467011, 9600246, 20926450]. Functional studies indicate this variant impacts protein function [PMID: 10866302]. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 16, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 17, 2016	- -

Macrocephaly-autism syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Oct 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -

PTEN hamartoma tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2023

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 68 of the PTEN protein (p.Tyr68His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cowden syndrome (PMID: 9467011, 9600246, 19457929, 20926450, 25288137, 25669429, 25722288). ClinVar contains an entry for this variant (Variation ID: 189474). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302, 19457929, 20926450). 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: 19457929, 21956414, 24778394, 26246517). 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

Aug 01, 2019

Published functional studies demonstrate a damaging effect: significantly reduced phosphatase activity, decreased protein expression, and increased nuclear localization (Han 2000, Lobo 2009, He 2011, Mighell 2018); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29970488, 26246517, 19457929, 25669429, 20926450, 10866302, 9467011, 21659347, 25722288, 11494117, 10400993, 9600246, 24778394, 21956414, 31055886, 31006514, 29663862, 29706350, 25288137, 24475377, 32665702) -

Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 24, 2021

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2021

The p.Y68H variant (also known as c.202T>C), located in coding exon 3 of the PTEN gene, results from a T to C substitution at nucleotide position 202. The tyrosine at codon 68 is replaced by histidine, an amino acid with similar properties. This variant has been identified in individuals meeting clinical diagnostic criteria for Bannayan-Zonana syndrome (BZS) and Cowden syndrome (Marsh DJ. Hum Mol Genet. 1998 Mar;7(3):507-15; Tsou HC et al. Hum. Genet. 1998 Apr;102:467-73; Lobo, GP. Hum Mol Genet. 2009 Aug 1;18(15):2851-62; Cooiman MI et al. Mol Genet Genomic Med. 2019 Jun;7:e00632), and another patient with suspected PTHS (Pilarski, R. J Med Genet. 2011 Aug;48(8):505-12). Functional and structural analyses have demonstrated that this variant produces no phosphatase activity and impairs PTEN protein function, localization and stability (Georgescu MM et al. Cancer Res. 2000 Dec;60:7033-8; Han SY et al. Cancer Res. 2000 Jun;60:3147-51; Lobo, GP. Hum Mol Genet. 2009 Aug 1;18(15):2851-62; He X. Hum Mol Genet. 2011 Jan 1;20(1):80-9; Matreyek KA et al. Nat. Genet. 2018 06;50:874-882; Smith IN et al. J. Biomol. Struct. Dyn. 2019 Apr;37:1766-1782; Smith IN et al. Am. J. Hum. Genet. 2019 May;104:861-878; Mighell TL et al. Am J Hum Genet. 2018 05;102:943-955). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is completely conserved on sequence alignment. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Glioma susceptibility 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 28, 2023

- -

Macrocephaly-autism syndrome;CN072330:Cowden syndrome 1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

-

Variant interpreted as Pathogenic and reported on 01-13-2021 by Lab Prevention Genetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.018	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.93		Gain of disorder (P = 0.0256);
MVP		0.99
MPC		2.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.88
gMVP		0.98

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: rs398123317; hg19: chr10-89685307; COSMIC: COSV64289561;