PTEN c.808del, p.Met270CysfsTer6
NM_000314.8:c.808del
COSMIC ID: COSM6923288
Pathogenic
The c.808del (M270Cfs*6) variant in PTEN is a truncating loss‐of‐function change, meeting VCEP PVS1 Very Strong and PS3 Strong, with additional supporting PM2 and PP5, consistent with a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
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.808del
Protein Change
M270Cfs*6
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 270 in gene PTEN
Alternate Identifiers
COSM6923288
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.808del
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
Pathogenic
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 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 270 in gene PTEN
Functional Summary
The PTEN M270Cfs*6 variant is a truncating mutation that results in the loss of PTEN phosphatase function, impairing its ability to negatively regulate the PI3K/AKT pathway. Functional studies have demonstrated that such truncating mutations are oncogenic, leading to increased genomic instability due to the inability of PTEN to associate with chromosomal centromeres.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
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 Use PTEN PVS1 decision tree." The evidence for this variant shows: NM_000314.8:c.808del (M270Cfs*6) is a frameshift truncating variant in PTEN and is not in the last exon. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN PVS1 decision tree for a null variant in a gene where loss of function is a known mechanism of disease.
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: c.808del causes a frameshift rather than a previously established identical amino acid change. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "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." The evidence for this variant shows: no de novo occurrence data reported. Therefore, PS2 is not applied.
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 M270Cfs*6 abolishes PTEN phosphatase activity and leads to oncogenic effects. Therefore, PS3 is applied at Strong strength because well-established functional assays support a damaging effect on PTEN.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Very Strong Probands with specificity score ≥16 OR Strong Probands with specificity score 4–15.5..." The evidence for this variant shows: no case‐control or specificity score data. Therefore, PS4 is not applied.
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 and well‐established functional domain: residues in catalytic motifs 90–94, 123–130, 166–168." The evidence for this variant shows: codon 270 lies outside the defined catalytic motifs. Therefore, PM1 is not applied.
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 in gnomAD or other large population database." The evidence for this variant shows: absent from gnomAD (MAF = 0%). Therefore, PM2 is applied at Supporting strength because it is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Moderate For recessive disorders, detected in trans with a pathogenic variant, or in cis observations..." The evidence for this variant shows: PTEN-related disease is autosomal dominant and no trans observations. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Protein length changes due to in‐frame deletions/insertions in a non‐repeat region or stop‐loss variants." The evidence for this variant shows: c.808del causes a frameshift, not an in‐frame change. Therefore, PM4 is not applied.
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 change is pathogenic..." The evidence for this variant shows: this is a frameshift, not a missense change. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations..." The evidence for this variant shows: no presumed de novo data. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Strong Co-segregation with disease in ≥7 meioses..." The evidence for this variant shows: no family segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Missense variant in a gene with a low rate of benign missense variation where missense is a common mechanism of disease." The evidence for this variant shows: it is a frameshift, not a missense variant. Therefore, PP2 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: computational splicing tools indicate no splicing impact, and this is a frameshift variant. Therefore, PP3 is not applied.
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 phenotype information provided. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: reported as Pathogenic in ClinVar by two clinical laboratories. Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone gnomAD Filtering allele frequency >0.00056." The evidence for this variant shows: absent from gnomAD. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong gnomAD Filtering allele frequency from 0.000043 up to 0.00056." The evidence for this variant shows: absent from gnomAD. Therefore, BS1 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 a healthy or PHTS-unaffected individual..." The evidence for this variant shows: no homozygous observations. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, BS3 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, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Missense variant in a gene where only loss of function causes disease." The evidence for this variant shows: it is a truncating variant causing loss of function. Therefore, BP1 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 or likely pathogenic PTEN variant..." The evidence for this variant shows: no cis/trans observations reported. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is a frameshift outside a repetitive region. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: computational tools indicate no splicing impact, but the variant is a frameshift predicted to disrupt protein. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Variant found in a case with an alternate molecular basis for disease..." The evidence for this variant shows: no alternate molecular basis reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Reputable source recently reports variant as benign..." The evidence for this variant shows: no benign reports. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting A synonymous or intronic variant at or beyond +7/‐21 for which splicing algorithms predict no impact..." The evidence for this variant shows: it is a frameshift, not synonymous or intronic. Therefore, BP7 is not applied.