rs1114167666
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM4PP3PP5_Moderate
The NM_000314.8(PTEN):c.738_743del(p.Leu247_Pro248del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P246P) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
PTEN
NM_000314.8 inframe_deletion
NM_000314.8 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.62
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 Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000314.8
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000314.8.
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
Variant 10-87957953-GCCGTTA-G is Pathogenic according to our data. Variant chr10-87957953-GCCGTTA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428252.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.738_743del | p.Leu247_Pro248del | inframe_deletion | 7/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.1257_1262del | p.Leu420_Pro421del | inframe_deletion | 8/10 | ||
PTEN | NM_001304718.2 | c.147_152del | p.Leu50_Pro51del | inframe_deletion | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.738_743del | p.Leu247_Pro248del | inframe_deletion | 7/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 22, 2019 | The c.738_743delGTTACC variant (also known as p.L247_P248del) is located in coding exon 7 of the PTEN gene. This variant results from an in-frame deletion of GTTACC between nucleotide positions 738 and 743. This results in the deletion of a highly conserved leucine residue at codon 247 and a highly conserved proline residue at codon 248. This variant was identified in an individual meeting clinical diagnostic criteria for PTEN hamartoma tumor syndrome (Ambry internal data). This variant also demonstrated aberrant activity in cell viability assays (Ng PK et al. Cancer Cell, 2018 03;33:450-462.e10). Based on internal structural analysis, p.L247 and p.P248 reside within a β-sandwich on the C2 domain directed towards the phosphatase domain and the p.L247_P248del alteration results in a distortion of this β-sandwich significantly altering the surrounding residues (Lee JO et al. Cell, 1999 Oct;99:323-34). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). In addition, this alteration is predicted to be deleterious by PROVEAN in silico analysis (Choi Y et al., Bioinformatics 2015 Aug; 31(16):2745-7). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at