10-87894110-G-C
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000314.8(PTEN):c.164+1G>C variant causes a splice donor 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
PTEN
NM_000314.8 splice_donor
NM_000314.8 splice_donor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.42
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 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.2, offset of -5, new splice context is: gtaGTaagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 10-87894110-G-C is Pathogenic according to our data. Variant chr10-87894110-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 427583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87894110-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.164+1G>C | splice_donor_variant | ENST00000371953.8 | |||
PTEN | NM_001304717.5 | c.683+1G>C | splice_donor_variant | ||||
PTEN | NM_001304718.2 | c.-541+1G>C | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.164+1G>C | splice_donor_variant | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 27
GnomAD4 exome
Cov.:
27
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
PTEN hamartoma tumor syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Herman Laboratory, Nationwide Children's Hospital | Mar 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 28, 2022 | Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 11886535). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 427583). Disruption of this splice site has been observed in individuals with clinical features of PTEN-related conditions (PMID: 11886535, 23335809, 28526761; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 2 of the PTEN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2021 | The c.164+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 2 of the PTEN gene. This alteration was identified in 3/146 patients in a cohort of individuals with clinically diagnosed Cowden syndrome (CS) and a previously identified PTEN alteration or were the familial mutation positive family members of the individuals meeting CS criteria (Bubien V et al. J Med Genet, 2013 Apr;50:255-63). This alteration was identified in a 9-year-old male meeting clinical diagnosis of Bannayan-Riley-Ruvalcaba syndrome (Hansen-Kiss E et al. J Med Genet, 2017 07;54:471-478). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with Cowden syndrome-related disease (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Another alteration impacting the same donor site (c.164+1G>T) has been detected in an individual with Cowden syndrome or Cowden syndrome-like disease (Ngeow J et al. J Clin Oncol, 2014 Jun;32:1818-24). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at