PTEN c.900del, p.Ile300MetfsTer7
NM_000314.8:c.900del
COSMIC ID: COSM921143
Pathogenic
The PTEN c.900del (I300Mfs*7) variant is classified as Pathogenic based on PVS1 (Very Strong) and PS3 (Strong), supported by absence in population databases (PM2) and multiple reputable sources reporting pathogenicity (PP5), despite benign computational predictions (BP4).
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
BP4
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.900del
Protein Change
I300Mfs*7
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 300 in gene PTEN
Alternate Identifiers
COSM921143
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.900del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
2 publications
Pathogenic
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
5 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hamartoma tumour syndrome. Loss of function is the mechanism for null variants while missense variants have been proven to exert either a loss of function or dominant-negative mechanism (GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. In particular, PTEN-related Proteus syndrome has been described to be a highly variable disorder (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least three patients with Cowden syndrome and/or Bannayan-Riley-Ruvalcaba syndrome (PMID: 21659347). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
This sequence change creates a premature translational stop signal (p.Ile300Metfs*7) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Cowden syndrome and/or Bannayan-Riley-Ruvalcaba syndrome (PMID: 21659347). ClinVar contains an entry for this variant (Variation ID: 211972). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories).
Functional Impact
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 300 in gene PTEN
Functional Summary
The PTEN I300Mfs*7 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have shown that such truncating mutations are oncogenic, as they increase genome fragility and disrupt PTEN's association with chromosomal centromeres. This evidence supports a damaging effect of the variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 5.25
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: 'Very Strong Strength: Very Strong Use PTEN PVS1 decision tree.' The evidence for this variant shows: c.900del (I300Mfs*7) results in a premature stop codon leading to loss-of-function, and LOF is a known disease mechanism for PTEN. Therefore, this criterion is applied at Very Strong strength because this truncating variant is predicted to cause loss-of-function in PTEN.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: '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...' The evidence for this variant shows: it is a frameshift variant (I300Mfs*7), not an amino acid substitution matching a known pathogenic change. Therefore, this criterion is not applied because the variant does not produce 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: 'Strong: De novo (both maternity and paternity confirmed)...' The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied because there is no confirmed de novo occurrence in a patient.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: 'Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.' The evidence for this variant shows: functional studies demonstrate that I300Mfs*7 abolishes PTEN phosphatase activity and disrupts chromosomal association, supporting a damaging effect. Therefore, this criterion is applied at Strong strength because well-established functional assays show loss of PTEN function.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls.' The evidence for this variant shows: no case-control or proband count data are available. Therefore, this criterion is not applied due to lack of data on variant prevalence in affected individuals.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate: Located in a mutational hot spot and/or critical functional domain defined as residues 90-94, 123-130, 166-168.' The evidence for this variant shows: I300 is outside the defined catalytic motifs. Therefore, this criterion is not applied because the variant is not located in a known hot spot or critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting: Absent in population databases present at <0.00001 allele frequency.' The evidence for this variant shows: it is absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is not observed in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: no trans or compound heterozygous data are available. Therefore, this criterion is not applied due to lack of allelic phase data.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: 'Moderate: Protein length changes due to in-frame indels or stop-loss variants.' The evidence for this variant shows: it is a frameshift introducing a premature stop, covered by PVS1. Therefore, this criterion is not applied because PVS1 already addresses truncating variants.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Moderate: Missense change at a residue where a different missense pathogenic variant has been seen.' The evidence for this variant shows: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: 'Moderate: Assumed de novo without paternity/maternity confirmation.' The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied due to lack of de novo evidence.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting: Co-segregation with disease in multiple affected family members (3–4 meioses).' The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied due to lack of segregation data.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Supporting: Missense variant in a gene with low rate of benign missense variation where missense variants are common disease mechanism.' The evidence for this variant shows: it is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting: Multiple lines of computational evidence support a deleterious effect.' The evidence for this variant shows: CADD score 5.25 and SpliceAI 0.02, indicating minimal impact. Therefore, this criterion is not applied because computational predictions do not support a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting: Patient’s phenotype is highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no patient phenotype data are provided. Therefore, this criterion is not applied due to lack of phenotype information.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting: Reputable source reports variant as pathogenic without available evidence.' The evidence for this variant shows: ClinVar lists this variant as Pathogenic by five clinical laboratories. Therefore, this criterion is applied at Supporting strength because multiple reputable sources report pathogenicity without primary data.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone: Filtering allele frequency >0.00056.' The evidence for this variant shows: allele frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong: allele frequency from 0.000043 to 0.00056.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong: Observed in the homozygous state in healthy individuals.' The evidence for this variant shows: no homozygous observations in unaffected individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong: Functional studies show no damaging effect.' The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Strong: Lack of segregation in affected members of two or more families.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Supporting: Missense variant in gene where only LOF causes disease.' The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Supporting: Observed in trans with a pathogenic PTEN variant.' The evidence for this variant shows: no data on allelic phase with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting: In-frame indel in a repetitive region without known function.' The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Supporting: Multiple lines of computational evidence suggest no impact.' The evidence for this variant shows: CADD score 5.25 and SpliceAI 0.02, indicating no splicing impact. Therefore, this criterion is applied at Supporting strength because computational tools do not predict a deleterious effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Supporting: Variant found with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting: Reputable source reports variant as benign without available evidence.' The evidence for this variant shows: no reputable source reports benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Supporting: Synonymous or intronic variant with no predicted splicing impact.' The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.