PTEN c.361G>C, p.Ala121Pro
NM_000314.8:c.361G>C
COSMIC ID: COSM5214
Pathogenic
This missense variant A121P in PTEN is classified as Likely Pathogenic on the basis of Moderate evidence from well-established functional studies (PS3) and novel pathogenic residue change (PM5), along with supporting evidence from absence in population (PM2) and computational predictions (PP3).
ACMG/AMP Criteria Applied
PS3
PM2
PM5
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.361G>C
Protein Change
A121P
Location
Exon 5
(Exon 5 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 121: A121T, A121E, A121G
Alternate Identifiers
COSM5214
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.361G>C
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 2 submitter reviews in ClinVar
Submitter Breakdown
1 LP
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and 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 121: A121T, A121E, A121G
PM5 criterion applied.
Functional Summary
Loss-of-Function
The PTEN A121P variant has been functionally characterized and demonstrated to be inactivating. In vitro studies show that this mutation results in decreased protein phosphatase activity compared to the wildtype, indicating a loss-of-function effect. This variant is located in the phosphatase domain of PTEN and is associated with oncogenic activity in cancers such as brain and breast cancer.
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
0.912
0.912
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:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 6.07
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 Use PTEN PVS1 decision tree." This variant is a missense change (A121P), not a null variant. Therefore, this criterion is not applied because PVS1 applies only to predicted null variants.
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." There is no known pathogenic variant encoding A121P by any other nucleotide 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..." No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing, the finding for PS3_Moderate is: "Phosphatase activity score -1.9816 < threshold -1.11 per Mighell et al. 2018." The evidence for this variant shows in vitro studies with phosphatase activity below threshold, indicating damaging effect. Therefore, PS3 is applied at Moderate strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 requires case/control data or proband specificity scores. No case-level or prevalence data are available. 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 functional domain (residues 90-94, 123-130, 166-168)." Position 121 lies outside those 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 (gnomAD <0.001%)." The variant is absent from gnomAD and other large databases. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG, PM3 applies to recessive genes with trans observations. PTEN is autosomal dominant and no trans data are relevant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG, PM4 applies to in-frame indels or stop-loss variants. This is a missense change. Therefore, PM4 is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: "Moderate: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." A different pathogenic missense at residue 121 has been reported. Therefore, PM5 is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is de novo without confirmation. No presumed de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 requires segregation 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, PP2 applies when missense is common mechanism and gene has low benign missense rate. PTEN has diverse disease mechanisms and missense variation is not uniquely indicative. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting: Multiple lines of computational evidence support deleterious effect (REVEL >0.7)." This variant has a REVEL score of 0.91. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG, PP4 requires a highly specific phenotype. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG, PP5 is applied when a reputable source reports pathogenic without primary evidence. ClinVar entries are conflicting (Uncertain and Likely). Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies at allele frequency >0.056%. The variant is absent. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies at allele frequency 0.0043–0.056%. The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies to homozygous observations in healthy individuals. No such data exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires functional studies showing no damaging effect. Existing studies show damaging effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in affected members. No segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG, BP1 applies when missense variants in a gene with only truncating disease mechanism. PTEN missense variants are pathogenic. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 applies to observations in trans with pathogenic PTEN variants. No such data. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG, BP3 applies to in-frame indels in repeats. This is a missense variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 requires computational evidence suggesting no impact (REVEL <0.5). This variant has REVEL 0.91. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies when alternate molecular basis explains disease. No such context. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG, BP6 applies when a reputable source reports benign without evidence. No such report. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or deep intronic variants. This is missense. Therefore, BP7 is not applied.