10-87894049-T-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS2PS3PM2PP2
This summary comes from the ClinGen Evidence Repository: PTEN c.104T>G (p.Met35Arg) 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).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (PMID 9425889)PS3: Phosphatase activity <50% of wild type. (PMID 21828076, 25875300)PM2: Absent in large sequenced populations (PMID 27535533).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/CA000268/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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.104T>G | p.Met35Arg | missense_variant | 2/9 | ENST00000371953.8 | NP_000305.3 | |
PTEN | NM_001304717.5 | c.623T>G | p.Met208Arg | missense_variant | 3/10 | NP_001291646.4 | ||
PTEN | NM_001304718.2 | c.-602T>G | 5_prime_UTR_variant | 2/9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Cowden syndrome 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 06, 2023 | This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29785012]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 37819013, 9425889]. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2003 | - - |
PTEN hamartoma tumor syndrome Pathogenic:2
Pathogenic, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Jul 25, 2018 | PTEN c.104T>G (p.Met35Arg) 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (PMID 9425889) PS3: Phosphatase activity <50% of wild type. (PMID 21828076, 25875300) PM2: Absent in large sequenced populations (PMID 27535533). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 35 of the PTEN protein (p.Met35Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (PMID: 9425889). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7825). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 21828076, 25875300). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Met35 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 17526801, 26468640; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at