PTEN c.524T>C, p.Val175Ala
NM_000314.8:c.524T>C
COSMIC ID: COSM1349560
Variant of Uncertain Significance (VUS)
This variant is classified as VUS based on application of PM2 and PP3 only, with insufficient functional, familial, and epidemiological data to satisfy additional ACMG/PTEN criteria.
ACMG/AMP Criteria Applied
PM2
PP3
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.524T>C
Protein Change
V175A
Location
Exon 6
(Exon 6 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 175: V175M
Alternate Identifiers
COSM1349560
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.524T>C
Active Tracks
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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
Unknown
Publications (0)
No publication details.
Clinical Statement
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 175: V175M
PM5 criterion applied.
Functional Summary
The PTEN V175A variant has not been functionally characterized, and its effect on PTEN protein function is currently unknown.
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
0.932
0.932
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Pathogenic
PP3 Applied
Yes
Additional Predictors
Pathogenic:
sift: Dpolyphen_prediction: probably_damagingmutationtaster: Dfathmm: Dprovean: Dmetasvm: Dmetalr: Dprimateai: Ddeogen2: D
Benign:
CADD: 5.48
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Use PTEN PVS1 decision tree." The evidence for this variant shows: it is a missense change, not a null variant. Therefore, this criterion is not applied because the variant does not meet the PTEN PVS1 decision tree for loss-of-function.
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." The evidence for this variant shows: no previously established pathogenic variant results in p.V175A. Therefore, this criterion is not applied due to lack of matching pathogenic amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Strong Strength: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied due to absence of confirmed de novo occurrence.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: "Score (-0.7870) did not meet threshold (-1.11) for PS3_Moderate." The evidence for this variant shows: phosphatase activity score of -0.7870, above the PTEN VCEP moderate threshold. Therefore, this criterion is not applied because the variant does not demonstrate functional impact per PTEN VCEP PS3 criteria.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Probands with specificity score 4-15.5 OR prevalence significantly increased in affected vs controls." The evidence for this variant shows: no case-control or proband specificity data. Therefore, this criterion is not applied due to lack of epidemiological evidence.
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 (residues 90-94, 123-130, 166-168)." The evidence for this variant shows: p.V175A lies outside the defined catalytic motifs. Therefore, this criterion is not applied because the variant is not within a PTEN mutational hot spot or critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Absent in population Databases present at <0.00001 allele frequency in gnomAD." The evidence for this variant shows: MAF = 0% (absent from gnomAD). Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Moderate Strength: Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: no data on trans observations with a pathogenic PTEN variant. Therefore, this criterion is not applied due to lack of allelic phase information.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: Protein length changes due to in-frame deletions/insertions in a non-repeat region." The evidence for this variant shows: this is a missense change, not an in-frame indel. Therefore, this criterion is not applied because the variant does not alter protein length.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate Strength: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before, BLOSUM62 score criterion." The evidence for this variant shows: no other pathogenic missense variant reported at codon 175. Therefore, this criterion is not applied due to absence of a known pathogenic missense at this residue.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Strong Strength: Two presumed de novo occurrences with no family history." The evidence for this variant shows: no de novo or presumed de novo observations. Therefore, this criterion is not applied due to lack of de novo data.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting Strength: Co-segregation with disease in multiple affected family members (3-4 meioses)." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied due to absence of family segregation information.
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 and where missense variants are a common mechanism of disease." The evidence for this variant shows: insufficient data on background missense constraint in PTEN to apply. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect; Missense variants: REVEL score > 0.7." The evidence for this variant shows: REVEL = 0.93, plus multiple in silico tools predict damaging. Therefore, this criterion is applied at Supporting strength because computational evidence predicts deleterious impact.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting Strength: Phenotype specific for disease with single genetic etiology." The evidence for this variant shows: no phenotype or patient-specific information. Therefore, this criterion is not applied due to lack of clinical phenotype data.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: Variant previously reported as pathogenic by a reputable source without available evidence." The evidence for this variant shows: not present in ClinVar or other authoritative databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: gnomAD Filtering allele frequency >0.00056." The evidence for this variant shows: MAF = 0%, below threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: gnomAD Filtering allele frequency from 0.000043 up to 0.00056." The evidence for this variant shows: MAF = 0%, below this range. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Observed homozygous in a healthy/unaffected individual." The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: Well-established functional studies show no damaging effect." The evidence for this variant shows: functional impact unknown and PTEN pre-processing did not support non-damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation data and no family studies. 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 a gene where only truncating variants are known to cause disease." The evidence for this variant shows: PTEN missense variants can be pathogenic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: Observed in trans with a pathogenic PTEN variant OR in cis with multiple pathogenic variants." The evidence for this variant shows: no phase information or cis/trans data. 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 deletions/insertions in a repetitive region without functional impact." The evidence for this variant shows: this is a missense change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Multiple lines of computational evidence suggest no impact; Missense variants: REVEL < 0.5." The evidence for this variant shows: REVEL = 0.93, predictive of impact. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: Variant found in a case with an alternate highly penetrant molecular basis." The evidence for this variant shows: no alternate molecular diagnosis 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 as benign without evidence." The evidence for this variant shows: not reported in ClinVar or other sources. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Synonymous or intronic variant with no splicing impact." The evidence for this variant shows: this is a missense change. Therefore, this criterion is not applied.