rs121909226
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP2PS3PM2PS4_Supporting
This summary comes from the ClinGen Evidence Repository: PTEN c.209T>C (p.Leu70Pro) 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: Phosphatase activity <50% of wild type (PMID 29706350)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.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor(s) ClinVar Organization ID: 26957) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000350/MONDO:0017623/003
Frequency
Consequence
NM_000314.8 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.209T>C | p.Leu70Pro | missense_variant, splice_region_variant | 3/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.728T>C | p.Leu243Pro | missense_variant, splice_region_variant | 4/10 | ||
PTEN | NM_001304718.2 | c.-540-5489T>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.209T>C | p.Leu70Pro | missense_variant, splice_region_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
Cowden syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1998 | - - |
PTEN hamartoma tumor syndrome Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Jun 04, 2021 | PTEN c.209T>C (p.Leu70Pro) 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: Phosphatase activity <50% of wild type (PMID 29706350) 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor(s) ClinVar Organization ID: 26957) - |
Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 03, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 20, 2023 | The c.209T>C pathogenic mutation (also known as p.L70P), located in coding exon 3 of the PTEN gene, results from a T to C substitution at nucleotide position 209. The amino acid change results in leucine to proline at codon 70, an amino acid with similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with PTEN-related disease (Ambry internal data). 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)). 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 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at