chr10-87933147-C-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP2PM5PM1PS3PM2
This summary comes from the ClinGen Evidence Repository: PTEN c.388C>G (p.Arg130Gly) 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 10866302, PMID 21828076, PMID 29706350)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.PM2: Absent in large sequenced populations (PMID 27535533).PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 7829, SCV000840465.2).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/CA16602437/MONDO:0017623/003
Frequency
Consequence
NM_000314.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTEN | NM_000314.8 | c.388C>G | p.Arg130Gly | missense_variant | Exon 5 of 9 | ENST00000371953.8 | NP_000305.3 | |
| PTEN | NM_001304717.5 | c.907C>G | p.Arg303Gly | missense_variant | Exon 6 of 10 | NP_001291646.4 | ||
| PTEN | NM_001304718.2 | c.-363C>G | 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
Cowden syndrome 1 Pathogenic:2
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302,11051241, 20926450]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28677221, 24778394]. -
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PTEN hamartoma tumor syndrome Pathogenic:2
This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 130 of the PTEN protein (p.Arg130Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Cowden syndrome (PMID: 1945792). ClinVar contains an entry for this variant (Variation ID: 375958). 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: 10866302, 11948419, 21828076, 24292679). This variant disrupts the p.Arg130 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9915974, 10866302, 17942903, 21822720, 22327138, 23399955, 23470840; 22595938.). 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. -
PTEN c.388C>G (p.Arg130Gly) 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 10866302, PMID 21828076, PMID 29706350) PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. PM2: Absent in large sequenced populations (PMID 27535533). PM5: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic and with equal or lesser BLOSUM62 score has been seen before (ClinVar Variation ID 7829, SCV000840465.2). 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. -
not provided Pathogenic:1
This variant has been published in individuals with clinical features characteristic of a PTEN-related disorder (Lobo et al., 2009; Pilarski et al., 2011; Ngeow et al., 2014); Published functional studies demonstrate a damaging effect: loss of phosphatase activity, decreased protein expression, and nuclear mislocalization (Han et al., 2000; Koul et al., 2002; He et al., 2011; Rodriguez-Escudero et al., 2011; Nguyen et al., 2014; Papa et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31006514, 11948419, 24292679, 20926450, 21828076, 24766807, 29663862, 21659347, 31594918, 24778394, 19457929, 10866302, 29785012, 35386110, 10555148, 24475377, 34575870, 34649609) -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.R130G pathogenic mutation (also known as c.388C>G), located in coding exon 5 of the PTEN gene, results from a C to G substitution at nucleotide position 388. The arginine at codon 130 is replaced by glycine, an amino acid with dissimilar properties. 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 also demonstrated wild type-like intracellular protein abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). In other assays testing PTEN function, this variant showed functionally abnormal results (Lobo GP et al. Hum Mol Genet, 2009 Aug;18:2851-62; He X et al. Hum Mol Genet, 2011 Jan;20:80-9; Rodríguez-Escudero I et al. Hum Mol Genet, 2011 Nov;20:4132-42). Based on internal structural analysis, R130G disrupts an important position in the P-loop of PTEN, a motif critical for function disrupted by internally pathogenic variants (Han SY et al. Cancer Res, 2000 Jun;60:3147-51; Lee CU et al. Angew Chem Int Ed Engl, 2015 Nov;54:13796-800; Masson GR et al. Cold Spring Harb Perspect Med, 2020 03;10:). 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)). Another variant at the same codon, p.R130Q (c.389G>A), has been described in a number of individuals of varying backgrounds with classic features of PTEN Hamartoma Tumor Syndrome (PHTS) or early onset breast cancer (Kurose K et al. Am. J. Hum. Genet. 1999 Jan;64(1):308-10; Lobo GP et al. Hum. Mol. Genet., 2009 Aug;18:2851-62; Pilarski R et al. J. Med. Genet. 2011 Aug;48(8):505-12); Baig RM et al. Asian Pac. J. Cancer Prev. 2011;12(10):2773-8; Heindl M et al. Gastroenterology. 2012 May;142(5):1093-1096.e6; Busch RM et al. Genet. Med. 2013 Jul;15(7):548-53; Chen HH et al. J. Allergy Clin. Immunol., 2017 Feb;139:607-620.e15). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Endometrial carcinoma Pathogenic:1
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Neoplasm Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at