chr10-87933037-A-G
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000314.8(PTEN):c.278A>G(p.His93Arg) 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 Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H93P) 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.278A>G | p.His93Arg | missense_variant | 5/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.797A>G | p.His266Arg | missense_variant | 6/10 | ||
PTEN | NM_001304718.2 | c.-473A>G | 5_prime_UTR_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.278A>G | p.His93Arg | missense_variant | 5/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
PTEN hamartoma tumor syndrome Pathogenic:3
Pathogenic, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Nov 28, 2018 | PTEN c.278A>G (p.His93Arg) 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. (internal laboratory contributor(s) ClinVar Organization ID: 26957) 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). 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. PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 26579216, 25647146, 20718038, 21828076, 29373119, 29785012, 29706350) PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 15805158, internal laboratory contributor(s) ClinVar Organization ID: 26957) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 02, 2021 | This sequence change replaces histidine with arginine at codon 93 of the PTEN protein (p.His93Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His93 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9685848, 10866302, 21828076, 24778394). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects PTEN function (PMID: 20718038, 21828076, 22505997, 25647146, 26579216). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 7848). This missense change has been observed in individuals with clinical features of PTEN hamartoma tumor syndrome (PMID: 15805158, 24345843, 25647146). This variant is not present in population databases (ExAC no frequency). - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 11, 2020 | The p.His93Arg variant in PTEN has been reported in 2 individuals with clinical features of PTEN-associated disorders, including 1 de novo case with confirmed maternity and paternity (Butler 2005, Henderson 2014). It was absent from large population studies. Several in vitro and in vivo functional studies support an impact on protein function (Redfern 2010, Rodriguez-Escudero 2011, He 2015, Johnston 2015, Fricano-Kugler 2018, Matreyek 2018). In addition, computational prediction tools and conservation analyses are consistent with pathogenicity. Additionally, this variant was classified as pathogenic on 11/28/18 by the ClinGen-approved PTEN variant expert panel (Variation ID 7848). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant PTEN Hamartoma Tumor Syndrome. ACMG/AMP Criteria applied: PS2, PM2, PP2, PP3, PS3_Supporting, PS4_Supporting. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 09, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
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. Functional studies indicate this variant impacts protein function [PMID: 32350270, 20718038, 25647146]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2022 | The p.H93R variant (also known as c.278A>G), located in coding exon 5 of the PTEN gene, results from an A to G substitution at nucleotide position 278. The histidine at codon 93 is replaced by arginine, an amino acid with highly similar properties. In one study, this alteration was detected as a de novo occurrence (paternity confirmed) in an individual with macrocephaly (+8SD), macrosomia, severe speech delay, autistic behavior, adenoidectomy, ear infections, mild bilateral epicanthal folds, and a flattened nasal bridge (Butler MG et al. J. Med. Genet., 2005 Apr;42:318-21). This alteration has also been detected in an individual with PHTS (PTEN hamartoma tumor syndrome) and EGID (eosinophilic gastrointestinal disorders) (Henderson CJ et al. J. Pediatr. Gastroenterol. Nutr., 2014 May;58:553-60). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was defined as "wild-type like" (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955), and this variant demonstrated "possibly wild-type like" intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). However, in multiple other functional studies performed on this alteration, authors have found that this alteration reduces phosphatase activity (but does not completely eliminate it), reduces PTEN enzyme activity, and impacts membrane binding (Redfern RE et al. Protein Sci., 2010 Oct;19:1948-56; Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42; Johnston SB et al. Biochemistry, 2015 Feb;54:1576-82). This amino acid position is highly conserved in available vertebrate species. 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. - |
Macrocephaly-autism syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2005 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at