rs121909218
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000314.8(PTEN):c.386G>A(p.Gly129Glu) 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. G129R) has been classified as Pathogenic.
Frequency
Consequence
NM_000314.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.386G>A | p.Gly129Glu | missense_variant | 5/9 | ENST00000371953.8 | NP_000305.3 | |
PTEN | NM_001304717.5 | c.905G>A | p.Gly302Glu | missense_variant | 6/10 | NP_001291646.4 | ||
PTEN | NM_001304718.2 | c.-365G>A | 5_prime_UTR_variant | 4/9 | NP_001291647.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.386G>A | p.Gly129Glu | missense_variant | 5/9 | 1 | NM_000314.8 | ENSP00000361021.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cowden syndrome 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 28, 2023 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302, 10051603, 24766807]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 02, 1999 | - - |
PTEN hamartoma tumor syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly129 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9256433, 17928923, 22469695, 25527629, 28497778). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PTEN function (PMID: 10698713, 12075083, 12208743, 21828076, 22962422, 29706350, 29785012). 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. ClinVar contains an entry for this variant (Variation ID: 7812). This missense change has been observed in individuals with clinical features of PTEN hamartoma tumor syndrome (PMID: 9140396, 23399955). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 129 of the PTEN protein (p.Gly129Glu). - |
Pathogenic, criteria provided, single submitter | clinical testing | Herman Laboratory, Nationwide Children's Hospital | Mar 01, 2017 | - - |
Malignant tumor of urinary bladder Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory of Urology, Hospital Clinic de Barcelona | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 31, 2022 | Published functional studies demonstrate a damaging effect: loss of lipid phosphatase activity and inability to regulate the PI-3K pathway (Leslie 2000, Rodriguez-Escudero 2011, He 2012, Mighell 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26827793, 9600246, 21659347, 9811831, 10698713, 21828076, 22962422, 29706350, 9140396, 23399955, 19457929, 24475377, 10051603, 19915616, 9616126, 12208743, 11230179, 12414663, 12075083, 9467011, 10923032, 27477328, 28526761, 32003824) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 11, 2018 | The p.G129E pathogenic mutation (also known as c.386G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 386. The glycine at codon 129 is replaced by glutamic acid, an amino acid with similar properties. This mutation has been reported in multiple Cowden syndrome and Cowden syndrome-like families (Liaw D et al. Nat. Genet. 1997 May; 16(1):64-7; Ngeow J et al. Gastroenterology 2013 Jun; 144(7):1402-9, 1409.e1-5; Pilarski R et al. J. Med. Genet. 2011 Aug;48(8):505-12). This mutation is located in the P-catalytic loop of the PTEN protein and has been shown to result in a fully inactive protein by in vivo functional analysis using a heterologous yeast reconstitution system (Rodríguez-Escudero I et al. Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). Multiple functional studies have also shown that this mutation leads to loss of lipid phosphatase activity and compromised dephosphorylation of active AKT, both of which are crucial to its tumor suppressor function (He X et al. J. Clin. Endocrinol. Metab. 2012 Nov; 97(11):E2179-87; Kandasamy K et al. Cancer Res. 2002 Sep; 62(17):4929-37; Ramaswamy S et al. Proc. Natl. Acad. Sci. U.S.A. 1999 Mar; 96(5):2110-5; Leslie NR et al. Biochem. J. 2000 Mar;346 Pt 3:827-33). Based on the available evidence, this variant is classified as a pathogenic mutation. - |
Neoplasm Other:1
-, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at