PTEN c.973C>T, p.Leu325Phe
NM_000314.8:c.973C>T
COSMIC ID: COSM1349616
Likely Pathogenic
This variant is classified as Likely Pathogenic based on a strong functional impact (PS3), a novel missense at a known pathogenic residue (PM5), and supportive evidence from absence in controls (PM2), gene mechanism (PP2), and computational predictions (PP3).
ACMG/AMP Criteria Applied
PS3
PM2
PM5
PP2
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.973C>T
Protein Change
L325F
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 325: L325R, L325P
Alternate Identifiers
COSM1349616
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.973C>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
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
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).
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 325: L325R, L325P
PM5 criterion applied.
Functional Summary
The PTEN L325F variant has been functionally characterized and demonstrated to be inactivating. Experimental evidence shows that expression of this mutation in lung cancer cells results in increased downstream pathway activation compared to the wildtype, indicating a loss of 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
0.732
0.732
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
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.53
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: Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows: it is a missense change and not predicted to result in loss of function. Therefore, this criterion is not applied because the variant does not meet the loss-of-function criteria.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: 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, where in silico models predict impact equal to or greater than the known pathogenic variant." The evidence for this variant shows: no previously established pathogenic variant with the same amino acid change or splicing impact at c.973C>T. Therefore, this criterion is not applied because no identical amino acid change has been observed as pathogenic.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Strong Strength: Strong 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 reported de novo occurrence with confirmed parental testing. Therefore, this criterion is not applied because de novo data are absent.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong Strength: Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: published functional assays demonstrate that PTEN L325F is inactivating, leading to increased downstream pathway activation compared to wild-type. Therefore, this criterion is applied at Strong strength because well-established functional studies show a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Strong Probands with specificity score 4-15.5 OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls." The evidence for this variant shows: no case series or prevalence data in affected individuals. Therefore, this criterion is not applied due to lack of case/control frequency data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate Strength: Moderate Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168." The evidence for this variant shows: residue 325 is outside the defined catalytic motifs. Therefore, this criterion is not applied because the variant is not in a mutational hot spot or critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%)." The evidence for this variant shows: absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population cohorts.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Moderate Strength: Detected in trans with a pathogenic variant in a recessive disorder." The evidence for this variant shows: no reports of trans observations with another PTEN pathogenic variant. Therefore, this criterion is not applied due to absence of trans genotype data.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Moderate Strength: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: a single amino acid substitution with no change in protein length. Therefore, this criterion is not applied because no in-frame indel or extension is present.
PM5
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: "Moderate Strength: Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant." The evidence for this variant shows: residue L325 has been altered by a different missense change reported as pathogenic, and BLOSUM62 criteria are met. Therefore, this criterion is applied at Moderate strength because a novel change occurs at a residue with known pathogenic variation.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Strong Strength: Strong Two probands with presumed de novo occurrence (maternity/paternity not confirmed)..." The evidence for this variant shows: no presumed de novo cases reported. Therefore, this criterion is not applied due to lack of de novo assumption data.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting Strength: Supporting Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed." The evidence for this variant shows: no segregation studies reported. Therefore, this criterion is not applied due to absence of family segregation data.
PP2
PP2 (Supporting)
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Strength: Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: PTEN has low benign missense variation and disease is commonly caused by missense changes. Therefore, this criterion is applied at Supporting strength because the gene and variant type meet PP2 conditions.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Missense variants: REVEL score > 0.7." The evidence for this variant shows: REVEL score 0.73, MetaSVM and MetaLR predict deleterious. Therefore, this criterion is applied at Supporting strength because in silico tools concordantly predict a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Strength: Phenotype or family history highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no detailed patient phenotype or family history provided. Therefore, this criterion is not applied due to insufficient phenotype data.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Strength: Reputable source recently reports variant as pathogenic." The evidence for this variant shows: ClinVar classification is Uncertain Significance. Therefore, this criterion is not applied because no reputable source classifies it as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)." The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied because the variant is not frequent enough.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Strong gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)." The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied because the variant is absent, not within the BS1 frequency range.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual." The evidence for this variant shows: no homozygous observations in healthy individuals. Therefore, this criterion is not applied due to absence of homozygosity data.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." The evidence for this variant shows: functional studies demonstrate damaging effect, not lack thereof. Therefore, this criterion is not applied because functional data support damage.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: Strong Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation analysis in multiple families. Therefore, this criterion is not applied due to lack of segregation evidence.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: Missense variant in a gene for which primarily truncating variants cause disease." The evidence for this variant shows: PTEN disease mechanism includes both truncating and missense variants. Therefore, this criterion is not applied because missense is a known mechanism.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis..." The evidence for this variant shows: no cis/trans observations with other PTEN variants. Therefore, this criterion is not applied due to lack of phasing data.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: a missense substitution, not an 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 Strength: Supporting Multiple lines of computational evidence suggest no impact on gene or gene product. Missense variants: REVEL scores < 0.5." The evidence for this variant shows: REVEL score 0.73 above threshold. Therefore, this criterion is not applied because computational evidence supports deleteriousness.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: 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 due to lack of alternate etiology.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Strength: Reputable source reports variant as benign." The evidence for this variant shows: no reputable source classification as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Supporting A synonymous (silent) or intronic variant at or beyond +7/-21 ..." The evidence for this variant shows: a missense change, not silent/intronic. Therefore, this criterion is not applied.