chr10-87933234-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.475A>G(p.Arg159Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R159S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000314.8 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.475A>G | p.Arg159Gly | missense_variant | 5/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.994A>G | p.Arg332Gly | missense_variant | 6/10 | ||
PTEN | NM_001304718.2 | c.-276A>G | 5_prime_UTR_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.475A>G | p.Arg159Gly | 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
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 03, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 02, 2022 | 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: 24475377, 21194675, 29785012, 10555148, 21828076, 17942903, 31594918, 29706350) - |
PTEN hamartoma tumor syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 11, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTEN function (PMID: 17942903). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 186094). This missense change has been observed in individual(s) with clinical features of Cowden syndrome (PMID: 21194675, 31594918; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 159 of the PTEN protein (p.Arg159Gly). - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 05, 2024 | The p.R159G variant (also known as c.475A>G), located in coding exon 5 of the PTEN gene, results from an A to G substitution at nucleotide position 475. The arginine at codon 159 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in individuals with features of Cowden syndrome (Tan MH et al. Am J Hum Genet, 2011 Jan;88:42-56; Busch RM et al. Transl Psychiatry, 2019 Oct;9:253). Yeast studies have indicated that this alteration compromises PTEN protein function (Andrés-Pons A, Cancer Res. 2007 Oct; 67(20):9731-9). 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). However, this variant demonstrated wild type-like intracellular protein abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). Based on the crystal structure for the PTEN protein, Arg159 stabilizes the conformation of the catalytic p-loop and the glycine substitution is expected to disrupt this interaction (Lee JO, Cell 1999 Oct; 99(3):323-34; Rodríguez-Escudero I, Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). 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 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 majority of available evidence to date, this variant is likely to be pathogenic. - |
Cowden syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 05, 2019 | Variant summary: PTEN c.475A>G (p.Arg159Gly) results in a non-conservative amino acid change located in the phosphatase domain (IPR029023) 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 250998 control chromosomes (gnomAD). c.475A>G has been reported in the literature in at least one individual affected with Cowden Syndrome (CS) or CS-like phenotype (Tan_2011). These data do not allow clear conclusions about variant significance. One publication reported experimental evidence and demonstrated that the variant protein expressed in mammalian cells resulted in increased levels of Akt1 phosphorylation (Andres-Pons_2007). In addition, another variant affecting the same amino acid (R159T) was reported to be found in a patient affected with CS or CS-like phenotype (HGMD, Tan_2011), further supporting a functional role for the affected residue. One ClinVar submitter (evaluation after 2014) cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at