PTEN c.113C>T, p.Pro38Leu
NM_000314.8:c.113C>T
COSMIC ID: COSM3736937
Pathogenic
p.P38L in PTEN meets two Moderate (PS3, PM5) and three Supporting (PM2, PP3, PP5) criteria per VCEP guidelines, yielding a final classification of Likely 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.113C>T
Protein Change
P38L
Location
Exon 2
(Exon 2 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 38: P38T, P38R
Alternate Identifiers
COSM3736937
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.113C>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
1 publications
Likely Pathogenic
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
1 Path
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
The p.P38L variant (also known as c.113C>T), located in coding exon 2 of the PTEN gene, results from a C to T substitution at nucleotide position 113. The proline at codon 38 is replaced by leucine, an amino acid with similar properties. In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories) and as Pathogenic (1 clinical laboratories) and as Pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen expert panel.
Expert Panel Reviews
Pathogenic
Clingen PTEN Variant Curation Expert Panel, Clingen
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
33
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (33 mutations).
PM1 criterion applied.
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 38: P38T, P38R
PM5 criterion applied.
Functional Summary
The PTEN P38L variant has been functionally characterized and is associated with reduced phosphatase activity, as demonstrated in a yeast assay. This reduction in activity suggests a loss of PTEN protein function. Additionally, in vitro studies indicate that this variant confers resistance to the MAP2K1 inhibitor E6201 in a melanoma cell line, further supporting a damaging effect on PTEN function.
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
0.923
0.923
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: 7.05
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PVS1 criterion applies to loss-of-function variants in PTEN per the PVS1 decision tree. The evidence for this variant shows: NM_000314.8:c.113C>T (p.P38L) is a missense change, not a null variant. Therefore, this criterion is not applied because the variant type is not predicted to result in loss of function.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when the same amino acid change as a previously established pathogenic variant is observed. The evidence for this variant shows: p.P38L is not the same amino acid change as any established pathogenic PTEN variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires de novo occurrence (confirmed maternity and paternity). The evidence for this variant shows: no de novo information is available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing, the rule/finding for PS3 is: "Applied PS3_Moderate (Score -3.7724 < -1.11)". The evidence for this variant shows: well-established in vitro functional studies demonstrate phosphatase activity ≤ –1.11 threshold per Mighell et al. 2018. Therefore, this criterion is applied at Moderate strength because the phosphatase activity score meets the PTEN-specific threshold.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 requires increased prevalence in affected individuals or sufficient proband specificity score. The evidence for this variant shows: no case-control or proband specificity data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to residues in catalytic motifs 90–94, 123–130, or 166–168. The evidence for this variant shows: p.P38 is outside these defined critical domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD". The evidence for this variant shows: c.113C>T is not found in 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 standard ACMG guidelines, PM3 applies to variants observed in trans with a pathogenic variant in a recessive disorder. The evidence for this variant shows: PTEN-related disorders are haploinsufficient, and no trans data exist. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes due to in-frame indels or stop-loss variants. The evidence for this variant shows: c.113C>T is a missense change without length alteration. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: "Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before, and the BLOSUM62 score is equal to or less than the known variant." The evidence for this variant shows: p.P38 has known pathogenic changes (e.g., P38S) and the BLOSUM62 score for P→L (–3) is less than that for P→S (–1). Therefore, this criterion is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo occurrences without confirmation. The evidence for this variant shows: no de novo information is available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires co-segregation with disease in affected family members. The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to a missense variant in a gene with low benign missense variation and where missense is a common disease mechanism. The evidence for this variant shows: insufficient data on benign missense rate to confidently apply. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect; REVEL score >0.7 for missense variants." The evidence for this variant shows: REVEL score is 0.92, exceeding the threshold. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies when the patient’s phenotype or family history is highly specific for a PTEN-related disorder. The evidence for this variant shows: no clinical phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, PP5 applies when a reputable source reports the variant as pathogenic but evidence is not available for independent evaluation. The evidence for this variant shows: ClinVar entries from multiple clinical laboratories and Clingen expert panel classify the variant as pathogenic or likely pathogenic. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies at a stand-alone level for allele frequency >0.056%. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies when allele frequency is between 0.0043% and 0.056%. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies to observation of the variant in homozygous state in healthy individuals. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies when well-established functional studies show no damaging effect. The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies when lack of segregation is observed in affected members of multiple families. The evidence for this variant shows: no segregation analysis. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies when the gene disease mechanism is strictly truncating and missense variants are benign. The evidence for this variant shows: PTEN missense variants are known to be pathogenic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 applies when a variant is observed in trans or cis with a PTEN pathogenic variant in multiple observations. The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. The evidence for this variant shows: it is a missense change, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 applies when computational evidence suggests no impact (REVEL <0.5). The evidence for this variant shows: REVEL is 0.92, indicating deleterious effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when variant is found in a case with an alternate molecular basis. The evidence for this variant shows: no alternate molecular basis is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source reports a variant as benign without evidence. The evidence for this variant shows: no reputable benign classification. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 applies to synonymous or intronic variants predicted to have no splicing impact. The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.