rs762518389

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000314.8(PTEN):c.144C>A(p.Asn48Lys) variant causes a missense change. 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.72

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 17 ACMG points.

PM1

In a domain Phosphatase tensin-type (size 171) in uniprot entity PTEN_HUMAN there are 110 pathogenic changes around while only 5 benign (96%) in NM_000314.8

PM2

Very rare variant in population databases, with high coverage;

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, 0.989

PP5

Variant 10-87894089-C-A is Pathogenic according to our data. Variant chr10-87894089-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 580731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87894089-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PTEN	NM_000314.8 linkuse as main transcript	c.144C>A	p.Asn48Lys	missense_variant	2/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 linkuse as main transcript	c.663C>A	p.Asn221Lys	missense_variant	3/10		NP_001291646.4
PTEN	NM_001304718.2 linkuse as main transcript	c.-562C>A		5_prime_UTR_variant	2/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.144C>A	p.Asn48Lys	missense_variant	2/9	1	NM_000314.8	ENSP00000361021	P1	P60484-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cowden syndrome 1

Pathogenic:1

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: 14675182, 25527629]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 14675182, 17526800, 21659347, 25527629]. -

PTEN hamartoma tumor syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 48 of the PTEN protein (p.Asn48Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PTEN hamartoma syndrome (PMID: 14675182, 17526800, 24498881, 25527629). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 580731). 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: 14675182, 17942903, 21828076, 24498881, 25527629). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2021

The p.N48K pathogenic mutation (also known as c.144C>A), located in coding exon 2 of the PTEN gene, results from a C to A substitution at nucleotide position 144. The asparagine at codon 48 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in individuals reported to meet clinical diagnostic criteria for Cowden syndrome (Vega A et al. J. Invest. Dermatol. 2003 Dec;121:1356-9; Morse CB et al. Gynecol. Oncol. Rep. 2015 Apr;12:13-6; Shon W et al. Br J Dermatol, 2014 May;170:1201-4). This alteration was reported as de novo in a 7-year-old child with clinical features of PTEN hamartoma tumor syndrome (Lachlan KL et al. J. Med. Genet. 2007 Sep;44:579-85). This alteration was also reported in several individuals suspected of having Cowden syndrome (Pilarski R et al. J. Med. Genet. 2011 Aug;48:505-12; Nieuwenhuis MH et al. Fam. Cancer 2014 Mar;13:57-63; Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43). In a functional study using a yeast-based assay, this variant demonstrated severely reduced phosphatase activity when compared to wild type PTEN and was similar to the catalytic dead control (Rodríguez-Escudero I et al. Hum. Mol. Genet. 2011 Nov;20:4132-42). In several studies, this variant showed normal protein expression that was comparable to wild type PTEN, but demonstrated reduced PTEN function (Vega A et al. J. Invest. Dermatol. 2003; Andrés-Pons A et al. Cancer Res. 2007 Oct;67:9731-9 Dec;121:1356-9; Spinelli L et al. J. Med. Genet. 2015 Feb;52:128-34). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (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 highly conserved in available vertebrate species. 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)). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Glioma susceptibility 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.91

Loss of stability (P = 0.0126);

MVP

0.98

MPC

3.7

ClinPred

1.0

GERP RS

5.2

Varity_R

0.93

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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