10-87933154-G-A
Variant summary
Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP2PS4PS3PM2PM6
This summary comes from the ClinGen Evidence Repository: PTEN c.395G>A (p.Gly132Asp) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 29706350, PMID 32350270)PS4: Probands with phenotype specificity score of 4-15.5 (PMID 25288137, PMID 23335809, PMID 23470840, internal laboratory contributor(s) SCV000279163)PM2: Absent in large sequenced populations (PMID 27535533)PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000279163)PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000444/MONDO:0017623/003
Frequency
Consequence
NM_000314.8 missense
Scores
Clinical Significance
Conservation
Publications
- Cowden syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
- PTEN hamartoma tumor syndromeInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- macrocephaly-autism syndromeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
- renal cell carcinomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- leiomyosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- activated PI3K-delta syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Bannayan-Riley-Ruvalcaba syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Cowden diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Lhermitte-Duclos diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Proteus-like syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- glioma susceptibility 2Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 13 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTEN | NM_000314.8 | c.395G>A | p.Gly132Asp | missense_variant | Exon 5 of 9 | ENST00000371953.8 | NP_000305.3 | |
| PTEN | NM_001304718.2 | c.-356G>A | 5_prime_UTR_premature_start_codon_gain_variant | Exon 4 of 9 | NP_001291647.1 | |||
| PTEN | NM_001304717.5 | c.914G>A | p.Gly305Asp | missense_variant | Exon 6 of 10 | NP_001291646.4 | ||
| PTEN | NM_001304718.2 | c.-356G>A | 5_prime_UTR_variant | Exon 4 of 9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:4Uncertain:1
PTEN: PS2, PS4, PM1, PM2, PM5, PS3:Moderate, PP2, PP3, PP4 -
Published functional studies demonstrate a damaging effect: loss of phosphatase activity (Mighell et al., 2018); 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: 25288137, 26919320, 23470840, 23335809, 22266152, 15120218, 20600018, 27477328, 27514801, 32037394, 33509259, 31594918, 19457929, 24475377, 27535533, 32350270, 33309985, 29706350) -
This variant has previously been reported in patients with PTEN hamartoma tumor syndrome (PHTS), which includes Cowden syndrome (CS, MIM: 158350) and Bannayan-Riley-Ruvalcaba syndrome (BRRS), all of which have significant clinical overlap (PMID: 15120218, PMID: 22266152, PMID: 23470840, PMID: 25288137). -
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The PTEN c.395G>A (p.Gly132Asp) variant has been reported in the published literature in individuals affected with PTEN Hamartoma Tumor syndrome (PMID: 15120218 (2004), 20600018 (2010), 23335809 (2013), and 25527629 (2015)) and autism spectrum disorder (PMID: 25288137 (2015)). This variant has also been reported to have a deleterious effect on PTEN protein function (PMID: 29706350 (2018), 32350270 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
PTEN hamartoma tumor syndrome Pathogenic:4
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 132 of the PTEN protein (p.Gly132Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with PTEN hamartoma tumor syndrome (PMID: 20600018, 22266152, 23335809, 23470840, 27477328). ClinVar contains an entry for this variant (Variation ID: 92822). 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: 29706350). This variant disrupts the p.Gly132 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16752378, 16773562, 21659347). 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. -
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid (exon 5). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region) (DSPc - dual specificity phosphatase, catalytic domain; Decipher, PDB). (P) 0702 - Comparable variants have strong previous evidence for pathogenicity. Multiple alternative change at the same residue, to valine, alanine, serine and phenylalanine, have previously been reported as pathogenic in patients with PTEN-related syndromes (ClinVar, HGMD, LOVD, PMID: 16752378, PMID: 17526801, PMID: 29806868, PMID: 27489861). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple patients with PTEN-related syndromes (ClinVar, HGMD, LOVD, PMID: 23335809, PMID: 23470840, PMID: 25288137, PMID: 31594918). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
PTEN c.395G>A (p.Gly132Asp) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3: Phosphatase activity <50% of wild type (PMID 29706350, PMID 32350270) PS4: Probands with phenotype specificity score of 4-15.5 (PMID 25288137, PMID 23335809, PMID 23470840, internal laboratory contributor(s) SCV000279163) PM2: Absent in large sequenced populations (PMID 27535533) PM6: Assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history. (Internal laboratory contributor(s) SCV000279163) PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. -
Variant summary: PTEN c.395G>A (p.Gly132Asp) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain (IPR003595) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251384 control chromosomes (gnomAD). c.395G>A has been reported in the literature in individuals affected with PTEN Hamartoma Tumor Syndrome as well as Cowden syndrome (example: Bubien_2014, Busch_2013, Chen_2017, Derrey_2004, Heald_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cite the variant as likely pathogenic/pathogenic or uncertain significance. An expert panel (ClinGen PTEN Variant Curation Expert Panel) also cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Cowden syndrome 1 Pathogenic:2
This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22266152, 21194675, 23335809, 16752378, 16773562, 17526801]. -
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Hereditary cancer-predisposing syndrome Pathogenic:1
The p.G132D variant (also known as c.395G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 395. The glycine at codon 132 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported in several individuals that either met clinical criteria for PTEN hamartoma tumor syndrome (PHTS) or had features consistent with PHTS (Heindl M et al. Gastroenterology, 2012 May;142:1093-1096.e6; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; Busch RM et al. Genet. Med., 2013 Jul;15:548-53; Frazier TW et al. Mol. Psychiatry, 2015 Sep;20:1132-8; Chen HH et al. J. Allergy Clin. Immunol., 2017 Feb;139:607-620.e15). 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(5):943-955). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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)). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Glioma susceptibility 2 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at