PTEN c.287C>T, p.Pro96Leu
NM_000314.8:c.287C>T
COSMIC ID: COSM5090
Likely Pathogenic
Likely Pathogenic classification based on two Moderate criteria (PS3, PM5) and three Supporting criteria (PM2, PP3, PP5) in accordance with PTEN-specific VCEP guidelines.
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.287C>T
Protein Change
P96L
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 96: P96A, P96S, P96R
Alternate Identifiers
COSM5090
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.287C>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
3 publications
Likely Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
1 Path
2 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 96 of the PTEN protein (p.Pro96Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTEN-related conditions. ClinVar contains an entry for this variant (Variation ID: 449089). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 29706350). This variant disrupts the p.Pro96 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11918710, 17942903, 21828076; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
The p.P96L variant (also known as c.287C>T), located in coding exon 5 of the PTEN gene, results from a C to T substitution at nucleotide position 287. The proline at codon 96 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 05;102:943-955). Based on internal structural analysis, the p.P96L alteration demonstrated disruption to the PTEN phosphatase domain (Ambry internal data; Lee CU et al. Angew Chem Int Ed Engl, 2015 Nov;54:13796-800; Dempsey DR et al. Nat Struct Mol Biol, 2021 10;28:858-868). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
The PTEN c.287C>T (p.Pro96Leu) variant has been reported to have a deleterious effect on PTEN protein function (PMID: 29706350 (2018)). In addition, a different variant located at the same position (PTEN c.287C>A (p.Pro96Gln)) has been reported to partial PTEN protein activity and expression (PMID: 17942903 (2007)) and has been reported in an individual with Cowden Syndrome (PMID: 11918710 (2002)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as likely pathogenic (1 clinical laboratories) and as Likely Pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen expert panel.
Expert Panel Reviews
Likely Pathogenic
Clingen PTEN Variant Curation Expert Panel, Clingen
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 96: P96A, P96S, P96R
PM5 criterion applied.
Functional Summary
The PTEN P96L variant has not been functionally characterized, and its effect on PTEN protein function is unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.933
0.933
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: Dmutationassessor: Hfathmm: Dprovean: Dmetasvm: Dmetalr: Dprimateai: Ddeogen2: D
Benign:
CADD: 6.00
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines: PVS1 applies to null variants per PTEN PVS1 decision tree. The rule for PVS1 is: Very Strong use for predicted null variants in PTEN. The evidence for this variant shows it is a missense change (c.287C>T; P96L). Therefore, this criterion is not applied because it does not create a predicted null allele.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: PS1 Strong strength when the same amino acid change as a known pathogenic variant is observed. The evidence for this variant shows P96L is novel and no identical amino acid change has been established as pathogenic. Therefore, this criterion is not applied because there is no previous pathogenic variant with the same amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines: PS2 requires confirmed de novo occurrence. The evidence for this variant shows no reports of de novo occurrence with parental confirmation. Therefore, this criterion is not applied due to lack of de novo data.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing: PS3 Moderate evidence based on phosphatase activity ≤ -1.11 per Mighell et al. 2018. The finding for PS3 is: phosphatase activity score -2.4794 < threshold -1.11. The evidence for this variant shows a high-confidence functional score of -2.4794. Therefore, this criterion is applied at Moderate strength because the functional impact meets the PTEN-specific threshold.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: PS4 requires an increased prevalence in affected individuals or proband specificity scores. The evidence for this variant shows no case-control or proband specificity data. Therefore, this criterion is not applied due to missing prevalence data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines: PM1 Moderate applies if the variant is located in a defined hotspot or functional domain (residues 90-94, 123-130, 166-168). The evidence for this variant shows residue P96 is outside these regions. Therefore, this criterion is not applied because the variant is not in a PTEN-defined hotspot or critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: PM2 Supporting when absent from population databases at <0.00001 allele frequency. The rule for PM2 is: absent in gnomAD or other large populations. The evidence for this variant shows it is not found in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: PM3 applies to recessive disorders when observed in trans with a pathogenic variant. The evidence for this variant shows no data on trans observations or biallelic inheritance. Therefore, this criterion is not applied due to missing trans inheritance data.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: PM4 Moderate applies to in-frame indels or protein length changes. The evidence for this variant shows it is a single amino acid substitution without affecting length. Therefore, this criterion is not applied because the variant does not alter protein length.
PM5
PM5 (Moderate)
According to VCEP guidelines: PM5 Moderate for a novel missense change at a residue where a different pathogenic missense has been seen. The rule for PM5 is: Missense change at an amino acid residue with a known pathogenic missense and BLOSUM62 score ≤ known variant. The evidence for this variant shows P96 is altered and other pathogenic changes at this residue have been reported. Therefore, this criterion is applied at Moderate strength because the residue has prior pathogenic missense changes.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines: PM6 requires presumed de novo occurrence without parent confirmation. The evidence for this variant shows no reports of de novo occurrences. Therefore, this criterion is not applied due to lack of de novo data.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: PP1 applies with co-segregation in multiple affected family members. The evidence for this variant shows no segregation data. Therefore, this criterion is not applied due to absence of family segregation data.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP2 Supporting for missense variants in genes with low benign variation and where missense is a common disease mechanism. The evidence for this variant shows PTEN has both missense and truncating pathogenic variants, but specific data on benign variation rate is lacking. Therefore, this criterion is not applied due to insufficient evidence on benign missense variation.
PP3
PP3 (Supporting)
According to VCEP guidelines: PP3 Supporting when REVEL score >0.7 for missense variants. The rule for PP3 is: REVEL score >0.7. The evidence for this variant shows REVEL=0.93. Therefore, this criterion is applied at Supporting strength because computational evidence strongly predicts deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines: PP4 Supporting for highly specific phenotype with single genetic etiology. The evidence for this variant shows no patient phenotype data. Therefore, this criterion is not applied due to missing phenotype specificity.
PP5
PP5 (Supporting)
According to standard ACMG guidelines: PP5 Supporting when a reputable source reports the variant as pathogenic without available evidence. The rule for PP5 is: ClinVar or expert panel reports. The evidence for this variant shows ClinVar and ClinGen PTEN VCEP report pathogenic/likely pathogenic. Therefore, this criterion is applied at Supporting strength because reputable sources classify it as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: BA1 Stand Alone for allele frequency >0.00056. The evidence for this variant shows allele frequency=0%. Therefore, this criterion is not applied because the variant is not common in population databases.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: BS1 Strong for allele frequency between 0.000043 and 0.00056. The evidence for this variant shows allele frequency=0%. Therefore, this criterion is not applied because frequency does not meet benign thresholds.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: BS2 applies when observed homozygous in healthy individuals. The evidence for this variant shows no homozygous observations. Therefore, this criterion is not applied due to lack of homozygous data.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: BS3 applies when functional studies show no damaging effect. The evidence for this variant shows damaging functional impact. Therefore, this criterion is not applied because studies indicate a deleterious effect.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: BS4 applies with lack of segregation in families. The evidence for this variant shows no segregation data. Therefore, this criterion is not applied due to absence of segregation evidence.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP1 Supporting for missense variants in genes where only truncating variants cause disease. The evidence for this variant shows PTEN has known pathogenic missense variants. Therefore, this criterion is not applied because missense is a known disease mechanism.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: BP2 applies when observed in trans with a pathogenic variant or in cis with several. The evidence for this variant shows no such observations. Therefore, this criterion is not applied due to missing allelic phase data.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP3 Supporting for in-frame indels in repetitive regions. The evidence for this variant shows a single amino acid substitution. Therefore, this criterion is not applied because it is not an in-frame indel.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines: BP4 Supporting when computational evidence predicts no impact (REVEL<0.5). The evidence for this variant shows REVEL=0.93. Therefore, this criterion is not applied because computational tools predict deleterious effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP5 Supporting for variant found with an alternate molecular basis. The evidence for this variant shows no alternate molecular basis reported. Therefore, this criterion is not applied due to lack of alternate genetic findings.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP6 Supporting for reputable source reporting benign variant without evidence. The evidence for this variant shows no reputable benign classification. Therefore, this criterion is not applied because no source reports benign.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines: BP7 Supporting for silent or intronic variants with no splicing impact. The evidence for this variant shows a missense change. Therefore, this criterion is not applied because it is not synonymous or intronic.