PTEN c.641A>C, p.Gln214Pro
NM_000314.8:c.641A>C
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Uncertain Significance (VUS)
0 publications
REVEL Score
0.779
Likely Pathogenic
COSMIC Recurrence
0 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.641A>C
Protein Change
Q214P
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 214 in gene PTEN
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
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories).
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 214 in gene PTEN
Functional Studies
Summary
The PTEN Q214P variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.779
0.779
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
mutationtaster: D
metasvm: D
metalr: D
Benign:
CADD: 4.69
primateai: T
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to VCEP guidelines: "Use PTEN PVS1 decision tree". The evidence for this variant shows it is a missense change (Q214P) not predicted to result in a null allele. Therefore, this criterion is not applied because PVS1 applies only to null variants.
PS1
PS1 (Not Applied)
Strength Modified
According to VCEP guidelines: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". There is no report of another variant causing Q214P in PTEN. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines: "De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history". No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to PTEN Pre-processing: "Score (-0.8550) did not meet threshold (-1.11) for PS3_Moderate". The evidence for this variant shows a phosphatase activity score of -0.8550 which is above the PTEN-specific threshold. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines: "Probands with specificity score ≥16 (Very Strong) or 4–15.5 (Strong) or 2–3.5 (Moderate) or 1–1.5 (Supporting)". No case/control data or proband specificity score are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines: "Located in a mutational hot spot and/or critical and well-established functional domain: residues 90-94, 123-130, 166-168". Q214 is outside these regions. Therefore, PM1 is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines: "Absent in population databases present at <0.00001 (0.001%) allele frequency in gnomAD". The evidence for this variant shows it is not found in gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied)
Strength Modified
According to VCEP guidelines: PM3 applies to recessive disorders for variants observed in trans with a pathogenic variant. PTEN-related conditions are autosomal dominant and no trans observations are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to VCEP guidelines: "Protein length changes due to in-frame deletions/insertions". This variant is a missense change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to VCEP guidelines: "Missense change at an amino acid residue where a different missense change determined to be pathogenic". No other pathogenic missense at residue 214 has been reported. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to VCEP guidelines: "Assumed de novo, but without confirmation of paternity and maternity". No de novo data exist. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines: "Co-segregation with disease in multiple affected family members". No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines: "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease". Insufficient gene-level benign variation data were provided to justify application. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines: "Missense variants: REVEL score > 0.7". The evidence for this variant shows a REVEL score of 0.78. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology". No phenotype data were provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines: "Reputable source classifies variant as pathogenic". ClinVar reports this variant as VUS, not pathogenic. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines: "gnomAD Filtering allele frequency >0.00056 (0.056%)". The variant is absent (AF=0%). Therefore, BA1 is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines: "gnomAD Filtering allele frequency 0.000043–0.00056". The variant is absent (AF=0%). Therefore, BS1 is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines: "Observed in homozygous state in a healthy individual". No homozygous observations exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines: "Well-established functional studies show no damaging effect". No such studies are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to VCEP guidelines: "Lack of segregation in affected members". No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines: "Missense variant in a gene where only truncating variants cause disease". PTEN disease mechanism includes missense variants. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to VCEP guidelines: "Observed in trans with a pathogenic PTEN variant". No trans observations exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines: "In-frame deletions/insertions in a repetitive region without a known function". This is a missense variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines: "Missense variants: REVEL score < 0.5". The REVEL score is 0.78. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to VCEP guidelines: "Variant found in a case with an alternate molecular basis for disease". No such case information is available. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines: "Reputable source classifies variant as benign". No reputable benign classification exists. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines: "Synonymous/intronic variant with no splicing impact". This is a missense variant. Therefore, BP7 is not applied.