rs398123316
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000314.8(PTEN):c.182A>G(p.His61Arg) 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. H61D) has been classified as Likely 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 | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.182A>G | p.His61Arg | missense_variant | 3/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.701A>G | p.His234Arg | missense_variant | 4/10 | ||
PTEN | NM_001304718.2 | c.-540-5516A>G | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.182A>G | p.His61Arg | missense_variant | 3/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Pathogenic:2Uncertain:1
Likely pathogenic, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Dec 01, 2023 | PTEN c.182A>G (p.His61Arg) meets criteria to be classified as likely 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_M: Massively parallel functional assay interrogating phosphatase activity demonstrating a statistically significant difference from wild type (PMID: 29706350). PS4_P: Proband(s) with phenotype specificity score of 1-1.5 (PMID: 28526761). PM2_P: 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. PP3: REVEL score = 0.981. - |
Pathogenic, criteria provided, single submitter | clinical testing | Herman Laboratory, Nationwide Children's Hospital | Mar 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302). 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: 189402). This missense change has been observed in individuals with clinical features of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (PMID: 20600018, 21194675, 21659347, 28526761). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 61 of the PTEN protein (p.His61Arg). - |
Neoplasm of ovary Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
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. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 24778394, 21659347, 21194675]. Functional studies indicate this variant impacts protein function [PMID: 10866302]. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 04, 2023 | The p.H61R variant (also known as c.182A>G) is located in coding exon 3 of the PTEN gene. This alteration results from an A to G substitution at nucleotide position 182. The histidine at codon 61 is replaced by arginine, an amino acid with similar properties. This alteration has been reported in individuals meeting relaxed International Cowden Consortium operational criteria for Cowden syndrome (Tan MH et al. Am J Hum Genet. 2011 Jan 7;88(1):42-56), as well as an individual with Bannayan-Riley-Ruvalcaba syndrome (Hansen-Kiss E et al. J. Med. Genet. 2017 07;54:471-478). 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 May;102:943-955). This variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). 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 mutation has also been reported at the same codon (p.H61D) in an individual with macrocephaly, ventricular dilatation, and features of VATER association (Reardon W et al. J Med Genet. 2001 Dec;38(12):820-3). This amino acid position is completely conserved on sequence alignment. The p.H61R variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at