PTEN c.731del, p.Pro244LeufsTer12
NM_000314.8:c.731del
COSMIC ID: COSM6926457
Pathogenic
This PTEN c.731del (p.P244Lfs*12) frameshift variant meets PVS1 (Very Strong) and PS3 (Strong) for LOF and damaging functional impact, along with PM2 and PP5 supporting pathogenicity. Despite computational evidence (BP4), the combined pathogenic evidence leads to a final classification of Pathogenic.
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.731del
Protein Change
P244Lfs*12
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 244 in gene PTEN
Alternate Identifiers
COSM6926457
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.731del
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
1 publications
Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This sequence change creates a premature translational stop signal (p.Pro244Leufs*12) 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 clinical features of PTEN hamartoma tumor syndrome (PMID: 21659347). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 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 244 in gene PTEN
Functional Summary
The PTEN P244Lfs*12 variant is a truncating mutation that results in the loss of PTEN phosphatase function. Functional studies have demonstrated that such truncating mutations lead to an inability to negatively regulate the PI3K/AKT pathway, contributing to oncogenic activity. Additionally, expression of PTEN truncation mutations in mouse embryonic fibroblasts has shown increased genome fragility due to impaired chromosomal centromere association. These findings support a damaging effect of the PTEN P244Lfs*12 variant.
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 Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific." The evidence for this variant shows a frameshift c.731del leading to a predicted loss‐of‐function in PTEN, a gene where LOF is a known mechanism of disease and the variant is not in the last exon. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP PTEN PVS1 decision tree for a null variant causing LOF.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: 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." The evidence for this variant shows a frameshift (P244Lfs*12), not the same amino acid change as any known pathogenic variant. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history." There are no de novo data available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong Strength: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. RNA, mini-gene, or other assay shows impact on splicing. Modification Type: Disease-specific." The PTEN Pre-processing finding is: "The PTEN P244Lfs*12 variant is a truncating mutation that results in the loss of PTEN phosphatase function; functional studies demonstrate inability to regulate PI3K/AKT pathway and increased genome fragility in mouse embryonic fibroblasts." Therefore, PS3 is applied at Strong strength because well-established functional studies support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Very Strong Strength: Probands with specificity score ≥16; Strong Strength: Probands with specificity score 4–15.5 or significant case-control data; etc." No case-control or proband specificity data are available for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate Strength: 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." This variant affects residue P244, outside those motifs. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population." The evidence shows the variant is absent from gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength because it is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 is for recessive disorders with variants observed in trans with a pathogenic variant. There is no evidence this variant occurs in trans in a recessive context. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 is: "Moderate Strength: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." This variant is a frameshift causing early truncation, not an in-frame change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 is: "Moderate Strength: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." This is a frameshift, not missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 is: "Very Strong/Strong/Moderate Strength: Assumed de novo observations without confirmation." No de novo evidence is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 is: "Supporting to Strong Strength: Co-segregation with disease in multiple affected family members." No segregation data are provided. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 is: "Supporting Strength: Missense variant in a gene with low benign missense variation and where missense variants are common mechanism." The variant is frameshift, not missense. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect (e.g., SpliceAI, REVEL)." Computational data (SpliceAI max score 0.01) show no predicted impact. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 is: "Supporting Strength: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, PP5 is: "Supporting Strength: Reputable source reports variant as pathogenic, but evidence is not available for independent evaluation." The evidence shows ClinVar lists this variant as Pathogenic from three clinical laboratories. Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 is: "Stand Alone Strength: gnomAD filtering allele frequency >0.00056 (0.056%)." The variant is absent from gnomAD (MAF=0%). Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 is: "Strong Strength: gnomAD filtering allele frequency from 0.000043 to 0.00056." The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 is: "Strong/Supporting Strength: Observed in homozygous state in healthy individuals." No homozygotes reported. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 is: "Strong/Supporting Strength: Well-established functional studies show no damaging effect." Functional studies demonstrate damaging effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 is: "Strong/Supporting Strength: Lack of segregation in affected members of families." No segregation data showing lack of co-segregation. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 is: "Supporting Strength: Missense variant in a gene where only LOF causes disease." The variant is frameshift (LOF), not missense. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 is: "Supporting Strength: Observed in trans with a pathogenic PTEN variant or multiple cis observations." No such observations are reported. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 is: "Supporting Strength: In-frame deletions/insertions in repetitive region without known function." The variant is a frameshift, not in a repeat region. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4 is: "Supporting Strength: Multiple lines of computational evidence suggest no impact on gene or gene product." Computational tools including SpliceAI show minimal impact (max score 0.01). Therefore, BP4 is applied at Supporting strength because predictions indicate no deleterious effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 is: "Supporting Strength: Variant found in a case with an alternate molecular basis for disease." No alternate molecular basis is reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 is: "Supporting Strength: Reputable source reports variant as benign." No reputable benign classification exists. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 is: "Supporting Strength: Synonymous or intronic variant with no predicted splicing impact." This variant is coding frameshift, not synonymous. Therefore, BP7 is not applied.