PTEN c.17A>T, p.Lys6Ile
NM_000314.8:c.17A>T
COSMIC ID: COSM40939
Pathogenic
This PTEN missense variant (K6I) is absent from population databases, affects a residue with a previously established pathogenic substitution, is predicted deleterious by computational tools, and has strong functional data demonstrating loss of activity. Combined with a reputable pathogenic report, these satisfy two Moderate (PS3, PM5) and three Supporting criteria (PM2, PP3, PP5), meeting ACMG thresholds for Pathogenic.
ACMG/AMP Criteria Applied
PS3
PM2
PM5
PP3
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.17A>T
Protein Change
K6I
Location
Exon 1
(Exon 1 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 6: K6E
Alternate Identifiers
COSM40939
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.17A>T
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
Likely Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (1 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
ClinVar reports other pathogenic variants at position 6: K6E
PM5 criterion applied.
Functional Summary
The PTEN K6I variant has been functionally characterized and is associated with a damaging effect. In vitro studies demonstrate that this mutation is oncogenic, showing suppression of anchorage-independent cell adhesion/survival, loss of lipid and protein phosphatase activities, and reduced protein stability compared to wild-type. Additionally, it leads to loss of PTEN function in yeast gene interaction assays, altered developmental rates in Drosophila, changes in rat neural development, and acts as a dominant negative regulator of the PI3-AKT signaling pathway.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.864
0.864
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
metasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 4.86polyphen_prediction: benign
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 rule: "Very Strong Use PTEN PVS1 decision tree." The evidence for this variant: it is a missense change (K6I) and does not create a null allele or affect canonical splice sites. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 rule: "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." The evidence for this variant: no identical amino acid substitution at K6 has been reported as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, PS2 rules: "Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations..." and "Strong De novo (both maternity and paternity confirmed) observation..." The evidence for this variant: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing, the finding for PS3_Moderate is: "Applied PS3_Moderate (Score -1.8883 < -1.11)". The evidence for this variant: well-established in vitro and in vivo functional studies demonstrate a phosphatase activity score of -1.8883, below the VCEP threshold of -1.11, indicating damaging effect. Therefore, this criterion is applied at Moderate strength because the functional score meets the PTEN-specific threshold.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 rule: "Strong Probands with specificity score 4-15.5... Moderate Probands with specificity score 2-3.5..." The evidence for this variant: no case or proband count data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 rule: "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." The evidence for this variant: K6 is outside of these defined critical motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 rule: "Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population." The evidence for this variant: not observed in gnomAD or other large control datasets. Therefore, this criterion is applied at Supporting strength because it is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 rule: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant: no trans allele data are available and PTEN disorders are autosomal dominant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, PM4 rule: "Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant: it is a missense change, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, PM5 rule: "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." The evidence for this variant: a different pathogenic missense at residue K6 has been reported, and the novel substitution has a BLOSUM62 score meeting the VCEP requirement. Therefore, this criterion is applied at Moderate strength because it meets the PTEN-specific PM5 conditions.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 rules: "Very Strong Two proven OR four assumed de novo... Strong Two probands with presumed de novo... Moderate Assumed de novo without confirmation..." The evidence for this variant: no de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 rule: "Supporting Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed." The evidence for this variant: no segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 rule: "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." The evidence for this variant: insufficient data on benign missense variation rate in PTEN for this specific residue. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, PP3 rule: "Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Missense variants: REVEL score > 0.7." The evidence for this variant: REVEL score is 0.86, exceeding the 0.7 threshold. Therefore, this criterion is applied at Supporting strength because multiple in silico tools predict a deleterious impact.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 rule: "Supporting Patient's phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant: no clinical phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, PP5 rule: "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: reported in ClinVar as Likely Pathogenic by a clinical laboratory without accessible primary data. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 rule: "Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)." The evidence for this variant: absent from gnomAD, frequency = 0. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 rule: "Strong gnomAD Filtering allele frequency from 0.000043 up to 0.00056." The evidence for this variant: absent from gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 rule: "Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual." The evidence for this variant: no homozygous observations in healthy individuals are reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 rule: "Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." The evidence for this variant: functional studies demonstrate damaging effects. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 rule: "Strong Lack of segregation in affected members of two or more families." The evidence for this variant: no segregation data demonstrating lack of cosegregation. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 rule: "Supporting Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant: PTEN has established pathogenic missense variants. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 rule: "Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis with different pathogenic variants." The evidence for this variant: no phase data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 rule: "Supporting In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant: it is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 rule: "Supporting Multiple lines of computational evidence suggest no impact on the gene or gene product. Missense variants: REVEL score < 0.5." The evidence for this variant: REVEL score is 0.86, indicating deleterious. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 rule: "Supporting Variant found in a case with an alternate molecular basis for disease." The evidence for this variant: no alternate molecular diagnosis is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 rule: "Supporting Reputable source reports variant as benign, but evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant: no reputable source reports this variant as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 rule: "Supporting A synonymous or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact." The evidence for this variant: it is a missense change. Therefore, this criterion is not applied.