PTEN c.710del, p.Lys237SerfsTer19
NM_000314.8:c.710del
COSM1684695
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Not Classified
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
1 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
PTEN
Transcript
NM_000314.8
MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000010.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 9 exons | Forward |
| NM_000314.5 | Alternative | 9 exons | Forward |
| NM_000314.4 | Alternative | 9 exons | Forward |
| NM_000314.3 | Alternative | 9 exons | Forward |
| NM_000314.6 | Alternative | 9 exons | Forward |
Variant Details
HGVS Notation
NM_000314.8:c.710del
Protein Change
K237Sfs*19
Location
Exon 7
(Exon 7 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 237 in gene PTEN
Alternate Identifiers
COSM1684695
Variant interpretation based on transcript NM_000314.8
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Not Classified
Publications
0 publications
Clinical Statement
Present in ClinVar, however no clinical evidence available for this variant.
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 237 in gene PTEN
Functional Studies
Summary
The PTEN K237Sfs*19 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway. Functional studies have shown that such truncating mutations are oncogenic, increasing genome fragility and disrupting PTEN's association with chromosomal centromeres.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "PVS1 - Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows: it is a frameshift truncating mutation (K237Sfs*19) in PTEN, a gene where loss of function is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because a null variant in PTEN meets the PVS1 decision tree requirements.
PS1
PS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS1 is: "PS1 - Strong Strength: Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant. Modification Type: Disease-specific". The evidence for this variant shows: it results in a frameshift and different amino acid sequence, not the same amino acid change as any known pathogenic variant. Therefore, PS1 is not applied because the variant does not meet the requirement of causing the same amino acid change as a known pathogenic variant.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS2 is: "PS2 - Very Strong Strength: Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history. Modification Type: Strength" and "Strong Strength: Strong De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. Modification Type: None". The evidence for this variant shows: no de novo occurrence data are available. Therefore, PS2 is not applied because there are no reported de novo observations.
PS3
PS3 (Strong)
According to PTEN pre-processing, the finding for PS3 is: "The PTEN K237Sfs*19 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway. Functional studies have shown that such truncating mutations are oncogenic, increasing genome fragility and disrupting PTEN's association with chromosomal centromeres." The evidence for this variant shows: well-established in vitro and in vivo functional studies confirm a damaging effect on PTEN. Therefore, PS3 is applied at Strong strength because functional studies specifically demonstrate a damaging effect on PTEN activity.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS4 is: "PS4 - Very Strong Strength: Very Strong Probands with specificity score ≥16 (see text). Modification Type: Strength; Strong Strength: Strong Probands with specificity score 4-15.5 or significant prevalence increase; Moderate Strength: Moderate Probands with specificity score of 2-3.5; Supporting Strength: Supporting Phenotype specific for disease with single genetic etiology. Proband(s) with specificity score of 1-1.5". The evidence for this variant shows: no case series or proband specificity scores available. Therefore, PS4 is not applied due to lack of reported patient frequency or specificity data.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM1 is: "PM1 - Moderate Strength: Moderate Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_000305.3). Modification Type: Disease-specific". The evidence for this variant shows: it occurs at residue 237, outside the defined catalytic motifs. Therefore, PM1 is not applied because the residue is not within a known critical functional domain.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines, the rule for PM2 is: "PM2 - Supporting Strength: Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%). Modification Type: Disease-specific". The evidence for this variant shows: it is not found in gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength because the variant is absent from population databases at the specified frequency threshold.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "PM3 - Moderate Strength: For recessive disorders, detected in trans with a pathogenic variant OR for homozygous variants". The evidence for this variant shows: PTEN-related disorders are autosomal dominant and no trans variant is reported. Therefore, PM3 is not applied because the variant is not observed in trans in a recessive context.
PM4
PM4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM4 is: "PM4 - Moderate Strength: Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif, and variants causing protein extension. Modification Type: Disease-specific". The evidence for this variant shows: it is a frameshift truncation, not an in-frame insertion/deletion or stop-loss. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM5 is: "PM5 - Moderate Strength: Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant. Modification Type: Disease-specific". The evidence for this variant shows: it is a frameshift variant, not a missense substitution. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM6 is: "PM6 - Very Strong Strength: Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history. Modification Type: Strength; Strong Strength: Strong Two probands with presumed de novo occurrence...; Moderate Strength: Moderate Assumed de novo... without confirmation.". The evidence for this variant shows: no de novo data available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP1 is: "PP1 - Supporting Strength: Supporting Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. Modification Type: Disease-specific; Moderate Strength: Moderate 5 or 6 meioses; Strong Strength: Strong ≥7 meioses.". The evidence for this variant shows: no segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP2 is: "PP2 - Supporting Strength: Supporting Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Modification Type: None". The evidence for this variant shows: it is a frameshift truncating variant, not a missense change. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP3 is: "PP3 - Supporting Strength: Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense variants: REVEL score > 0.7. Modification Type: Disease-specific". The evidence for this variant shows: only a low SpliceAI score of 0.07 and no other computational support. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "PP4 - Supporting Strength: Supporting Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.". The evidence for this variant shows: no specific phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "PP5 - Supporting Strength: Supporting A variant classified as pathogenic by a reputable source; original data not available for review.". The evidence for this variant shows: no authoritative source classification is available. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: "BA1 - Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)". The evidence for this variant shows: allele frequency is 0%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS1 is: "BS1 - Strong Strength: Strong gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)". The evidence for this variant shows: allele frequency is 0%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS2 is: "BS2 - Strong Strength: Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual...". The evidence for this variant shows: no homozygous observations are reported. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: "BS3 - Strong Strength: Strong Well-established in vitro or in vivo functional studies show no damaging effect on protein function.". The evidence for this variant shows: functional studies demonstrate a damaging effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS4 is: "BS4 - Strong Strength: Strong Lack of segregation in affected members of two or more families.". The evidence for this variant shows: no segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "BP1 - Supporting Strength: Supporting Missense variant in a gene for which primarily truncating variants are known to cause disease.". The evidence for this variant shows: it is a truncating frameshift variant. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP2 is: "BP2 - Supporting Strength: Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis...". The evidence for this variant shows: no data on trans or cis observations. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "BP3 - Supporting Strength: Supporting In-frame deletions/insertions in a repetitive region without a known functional domain.". The evidence for this variant shows: it is a frameshift truncating variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP4 is: "BP4 - Supporting Strength: Supporting Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense variants: REVEL scores < 0.5.". The evidence for this variant shows: functional data demonstrate a damaging effect despite a low SpliceAI score. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP5 is: "BP5 - Supporting Strength: Supporting Variant found in a case with an alternate molecular basis for disease.". The evidence for this variant shows: no alternate molecular basis is reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "BP6 - Supporting Strength: Supporting A variant classified as benign by a reputable source; original data not available for review.". The evidence for this variant shows: no benign classification from a reputable source is available. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP7 is: "BP7 - Supporting Strength: Supporting A synonymous or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact.". The evidence for this variant shows: it is a frameshift variant, not synonymous or intronic. Therefore, BP7 is not applied.