10-87933130-G-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000314.8(PTEN):c.371G>C(p.Cys124Ser) 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C124R) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
PTEN
NM_000314.8 missense
NM_000314.8 missense
Scores
17
1
1
Clinical Significance
Conservation
PhyloP100: 9.53
Genes affected
PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 23 ACMG points.
PS1
Transcript NM_000314.8 (PTEN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
PM1
In a mutagenesis_site Loss of protein phosphatase activity. Unable to inhibit focal adhesion formation. (size 0) in uniprot entity PTEN_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000314.8
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr10-87933129-T-C is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTEN. . Gene score misZ: 3.4883 (greater than the threshold 3.09). Trascript score misZ: 4.1129 (greater than threshold 3.09). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. GenCC has associacion of the gene with Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, macrocephaly-autism syndrome, Cowden syndrome 1, Cowden disease, Proteus-like syndrome, leiomyosarcoma, activated PI3K-delta syndrome, PTEN hamartoma tumor syndrome, glioma susceptibility 2, renal cell carcinoma.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 10-87933130-G-C is Pathogenic according to our data. Variant chr10-87933130-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2447220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87933130-G-C is described in Lovd as [Pathogenic]. Variant chr10-87933130-G-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PTEN | NM_000314.8 | c.371G>C | p.Cys124Ser | missense_variant | 5/9 | ENST00000371953.8 | NP_000305.3 | |
| PTEN | NM_001304717.5 | c.890G>C | p.Cys297Ser | missense_variant | 6/10 | NP_001291646.4 | ||
| PTEN | NM_001304718.2 | c.-380G>C | 5_prime_UTR_variant | 4/9 | NP_001291647.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cowden syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 27, 2023 | This variant is considered pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 17324556, 9256433, 20685300]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 24099866, 21194675]. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2023 | The p.C124S variant (also known as c.371G>C), located in coding exon 5 of the PTEN gene, results from a G to C substitution at nucleotide position 371. The cysteine at codon 124 is replaced by serine, an amino acid with dissimilar 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;88:42-56). This alteration was also observed in 1/7,051 unselected female breast cancer patients and was not observed with in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 Oct;9:4083). 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 "wild-type-like" 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)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
Glioma susceptibility 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 05, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of disorder (P = 5e-04);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.