10-87864539-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000314.8(PTEN):c.70G>C(p.Asp24His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D24G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 8.95

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PM1

In a strand (size 6) in uniprot entity PTEN_HUMAN there are 8 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 chr10-87864540-A-G is described in Lovd as [Pathogenic].

PP2

Missense variant in the PTEN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 3.4883 (above the threshold of 3.09). Trascript score misZ: 4.1129 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.991

PP5

Variant 10-87864539-G-C is Pathogenic according to our data. Variant chr10-87864539-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87864539-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.70G>C	p.Asp24His	missense_variant	Exon 1 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.589G>C	p.Asp197His	missense_variant	Exon 2 of 10		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.-636G>C		5_prime_UTR_variant	Exon 1 of 9		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.70G>C	p.Asp24His	missense_variant	Exon 1 of 9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461686

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727174

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Pathogenic:1

May 21, 2014

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cowden syndrome 1

Pathogenic:1

Dec 15, 2020

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

PTEN hamartoma tumor syndrome

Pathogenic:1

May 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Asp24 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21194675, 22503188). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 24 of the PTEN protein (p.Asp24His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features consistent with PTEN hamartoma tumor syndrome and/or PTEN-related conditions (PMID: 21194675, 24778394, 34308366; Invitae). ClinVar contains an entry for this variant (Variation ID: 186005). 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. Experimental studies have shown that this missense change affects PTEN function (PMID: 29706633). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Pathogenic:1

Jul 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in individuals with features of PTEN Hamartoma Tumor syndrome, including one apparently de novo observation (PMID: 34308366, 34374989, 22381246); Published functional studies demonstrate a damaging effect: impaired lipid phosphatase activity, aberrant cellular localization (PMID: 29706633, 29706350); 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; This variant is associated with the following publications: (PMID: 30626916, 21194675, 24778394, 33138866, 22381246, 23764071, 25669429, 24475377, 36453251, 29706633, 34308366, 34374989, 29706350) -

Glioma

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM6,PM3(strong),PM2,PP3,PM5 -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Dec 22, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D24H pathogenic mutation (also known as c.70G>C), located in coding exon 1 of the PTEN gene, results from a G to C substitution at nucleotide position 70. The aspartic acid at codon 24 is replaced by histidine, an amino acid with similar properties. This mutation has been identified in two separate females with the following similar Cowden syndrome/PHTS characteristics: pathognomonic dermatological features, breast cancer, uterine cancer, macrocephaly, multinodular goiter, and renal cell carcinoma (Mester JL, Urology 2012 May; 79(5):1187.e1-7; Shuch B, J. Urol. 2013 Dec; 190(6):1990-8). This mutation was also found in multiple individuals meeting clinical criteria for Cowden Syndrome (Tan MH, Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Ngeow J et al. J. Clin. Oncol., 2014 Jun;32:1818-2; Nizialek EA et al. Eur. J. Hum. Genet., 2015 Nov;23:1538-43). Further, an additional disease-causing mutation, p.D24N, has been described at this same codon. 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. -

Ovarian neoplasm

Pathogenic:1

Dec 01, 2018

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.97

Vest4

0.99

MutPred

0.89

Loss of stability (P = 0.0526);

MVP

1.0

MPC

3.9

ClinPred

1.0

GERP RS

5.3

Varity_R

0.90

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over