NM_000314.8:c.70G>T

Variant names:

• chr10-87864539-G-T
• rs786201995
• NM_000314.8:c.70G>T

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.70G>T​(p.Asp24Tyr) 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 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)
• Consequence: PTEN NM_000314.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.95

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 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, 0.994
• PP5: Variant 10-87864539-G-T is Pathogenic according to our data. Variant chr10-87864539-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 189398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87864539-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8	c.70G>T	p.Asp24Tyr	missense_variant	Exon 1 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5	c.589G>T	p.Asp197Tyr	missense_variant	Exon 2 of 10		NP_001291646.4
PTEN	NM_001304718.2	c.-636G>T		5_prime_UTR_variant	Exon 1 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8	c.70G>T	p.Asp24Tyr	missense_variant	Exon 1 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PTEN-related disorder Pathogenic:1

Jan 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PTEN c.70G>T variant is predicted to result in the amino acid substitution p.Asp24Tyr. This variant has been reported to have arisen de novo in one individual with Cowden syndrome (Tok Çelebi et al. 1999. PubMed ID: 10232405) and another individual with symptoms consistent with PTEN-related disease (Pelttari et al. 2018. PubMed ID: 28802053). This variant has not been reported in a large population database and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/189398/). Alternate nucleotide changes affecting the same amino acid (p.Asp24His, p.Asp24Gly, p.Asp24Asn) have been reported in individuals with Cowden syndrome and interpreted as pathogenic or likely pathogenic in ClinVar (Tan et al. 2011. PubMed ID: 21194675; Melbārde-Gorkuša et al. 2012 PubMed ID: 22503188; Pradella et al. 2014. PubMed ID: 24498881; ClinVar Variation IDs: 185200, 186005 and 208723). Taken together, this variant is interpreted as pathogenic. -

Cowden syndrome 1 Pathogenic:1

Sep 25, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10232405, 23335809]. Functional studies indicate this variant impacts protein function [PMID: 17213812]. -

not provided Pathogenic:1

Jul 13, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The D24Y missense variants in the PTEN gene has been reported previously in association with Bannayan-Riley-Ruvalcaba syndrome (Celebi et al., 1999). The D24Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in charge and size. This substitution occurs at a position that is highly conserved across species. Additionally, other missense variants in the same residue (D24H, D24V, D24G) have been reported, supporting the functional importance of this region of the protein. Furthermore, D24Y was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -

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	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.98
MutPred		0.94		Loss of phosphorylation at Y27 (P = 0.0831);
MVP		1.0
MPC		4.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.99

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

Other links and lift over

dbSNP: rs786201995; hg19: chr10-89624296; COSMIC: COSV64288588; COSMIC: COSV64288588;