PTEN c.125T>C, p.Leu42Pro
NM_000314.8:c.125T>C
COSMIC ID: COSM5112
Likely Pathogenic
Although the variant shows strong functional impairment (PS3_Moderate), absence from controls (PM2_Supporting), and deleterious computational predictions (PP3_Supporting), it does not meet the threshold for Likely Pathogenic per VCEP combining rules; thus it remains a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PS3
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.125T>C
Protein Change
L42P
Location
Exon 2
(Exon 2 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 42 in gene PTEN
Alternate Identifiers
COSM5112
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.125T>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
1 publications
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This variant has not been reported in the literature in individuals with PTEN-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 42 of the PTEN protein (p.Leu42Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant has been reported to affect PTEN protein function (PMID:25875300). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (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
No evidence of other pathogenic variants at position 42 in gene PTEN
Functional Summary
The PTEN L42P variant has been functionally characterized and is associated with reduced phosphatase activity in yeast assays, suggesting a loss of PTEN protein function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.948
0.948
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: 5.70
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." The evidence for this variant shows: it is a missense change (L42P) and not a predicted null (nonsense/frameshift/splice) variant. Therefore, this criterion is not applied because the variant does not meet loss‐of‐function null criteria.
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 OR different variant at same nucleotide position as a pathogenic splicing variant..." The evidence for this variant shows: no other PTEN variant with the same amino acid change (L42P) has been established as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Strong De novo (both maternity and paternity confirmed)..." The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Phosphatase activity ≤ -1.11 per Mighell et al. 2018 (score -2.4479)." The evidence for this variant shows: L42P has phosphatase activity score -2.4479, which is below the PTEN-specific threshold of -1.11. Therefore, this criterion is applied at Moderate strength because the functional assay meets the PTEN-specific moderate threshold.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines (no PTEN-specific rule), the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with controls or proband counts per VCEP specificity score." The evidence for this variant shows: no case‐control or proband aggregation data. Therefore, this criterion 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 and well-established functional domain: residues 90-94, 123-130, 166-168." The evidence for this variant shows: L42 is outside these defined catalytic motifs. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent in population Databases or present at <0.001% allele frequency in gnomAD." The evidence for this variant shows: not found in gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength due to absence from controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Moderate For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no evidence of occurrence in trans in a recessive context. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Moderate Protein length changes due to in-frame indels in non-repeat region." The evidence for this variant shows: the change is missense, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate Missense change at a residue where a different pathogenic missense has been seen, with BLOSUM62 score ≤ known variant." The evidence for this variant shows: no other pathogenic missense at position 42 in PTEN is reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Moderate Assumed de novo without confirmation of paternity/maternity." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting Co-segregation with disease in multiple affected family members (3-4 meioses)." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
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 is a common mechanism." The evidence for this variant shows: while PTEN missense can be pathogenic, no specific data about benign missense rate are provided. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting Multiple lines of computational evidence support a deleterious effect; REVEL score > 0.7." The evidence for this variant shows: REVEL = 0.95, multiple tools predict deleterious, SpliceAI low splicing effect. Therefore, this criterion is applied at Supporting strength for strong in silico support.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Patient’s phenotype or family history is highly specific for a disease with single genetic etiology." The evidence for this variant shows: no specific phenotype/family history data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: ClinVar lists as VUS. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone gnomAD Filtering allele frequency >0.056%." The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong gnomAD allele frequency 0.0043%–0.056%." The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Observed homozygous in healthy individuals." 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 Functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate reduced activity. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Missense in a gene where only truncating variants cause disease." The evidence for this variant shows: PTEN missense variants are known to cause disease. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Observed in trans with a pathogenic PTEN variant or multiple in cis." 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, the rule for BP3 is: "Supporting In-frame indels in repetitive region without functional impact." The evidence for this variant shows: missense, not in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Computational evidence suggests no impact; REVEL < 0.5." The evidence for this variant shows: REVEL = 0.95, predictions deleterious. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Supporting Variant found in a case with an alternate molecular basis for disease." 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 variant as benign without available evidence." The evidence for this variant shows: no benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Synonymous or intronic variant at +7/-21 with no splicing impact predicted." The evidence for this variant shows: non-synonymous missense. Therefore, this criterion is not applied.