About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.544T>G, p.(Leu182Val)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen PTEN VCEP v3.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Moderate
PS3 · moderate
L182V has a cumulative fitness score of -1.24 (Cum_SE=0.49, High_conf=True) in the Mighell et al. 2018 (PMID:29706350) massively parallel phosphatase activity saturation mutagenesis assay. This meets the PTEN VCEP PS3_Moderate threshold of Cum_score <= -1.11, indicating well-established in vitro functional evidence supportive of a damaging effect on protein function.
PM2Supporting
PM2 · supporting
NM_000314.8:c.544T>G is absent from gnomAD v2.1 and gnomAD v4.1 (0/1,612,242 alleles, AF=0.00000%). Per the PTEN VCEP specification, PM2 is applied at Supporting level for variants with allele frequency <0.00001 (0.001%) in gnomAD.
PP2Supporting
PP2 · supporting
PTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease (PTEN hamartoma tumor syndrome, autosomal dominant). PP2 is applicable per the PTEN VCEP specification for missense variants in PTEN.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: PS3 moderate, PM2 supporting, PP2 supporting; no rule matched the adjudicated criteria.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
0 / 1,612,242 alleles
gnomAD v4.1: 0 / 1,612,242 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV64288496, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PTEN VCEP v3.2.0, with the data and sources behind each one.
26 criteria with recorded statuses: 3 met · 16 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000314.8:c.544T>G (p.Leu182Val) is a missense variant in exon 6 of PTEN. It is absent from gnomAD v2.1 and v4.1 (0/1,612,242 alleles), meeting PM2_Supporting per the PTEN VCEP threshold of <0.001%.
In the Mighell et al. 2018 (PMID:29706350) saturation mutagenesis functional assay, L182V has a cumulative fitness score of -1.24 (High_conf=True), meeting the PTEN VCEP PS3_Moderate threshold of Cum_score <= -1.11, indicating a damaging effect on PTEN phosphatase activity.
PTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease (PHTS, autosomal dominant). PP2 is applied at Supporting level per the PTEN VCEP specification.
L182V REVEL score is 0.682, below the PTEN VCEP PP3 threshold of >0.7, and above the BP4 missense threshold of <0.5. Computational evidence is indeterminate and does not contribute to either pathogenic or benign criteria.
The variant lies outside PTEN catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168). PM1 is not met.
L182S (c.545T>C) is a pathogenic ClinVar missense at the same residue, but PM5 is not met because the BLOSUM62 score for Leu->Val (+1) is greater than Leu->Ser (-2), failing the VCEP BLOSUM62 requirement.
No proband, segregation, de novo, or case-control data are available. PS2, PS4, PM6, PP1, BS4, BP2, and BP5 are not met. Criteria not applicable per the PTEN VCEP include PVS1 (missense, not null), PP4, PP5, BP1, BP6, and BP7.
Overall, met criteria: PS3_Moderate (1 moderate), PM2_Supporting (1 supporting), PP2 (1 supporting). This yields 1 moderate + 2 supporting pathogenic criteria with no benign criteria. Under the PTEN VCEP/ACMG 2015 combination rules, Likely Pathogenic requires at least 3 moderate, or 2 moderate + >=2 supporting, or 1 strong + >=2 supporting, or 1 strong + 1 moderate. With only 1 moderate + 2 supporting, none of the Pathogenic or Likely Pathogenic rules are satisfied. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 3
PS3 ModerateL182V has a cumulative fitness score of -1.24 (Cum_SE=0.49, High_conf=True) in the Mighell et al. 2018 (PMID:29706350) massively parallel phosphatase activity saturation mutagenesis assay. This meets the PTEN VCEP PS3_Moderate threshold of Cum_score <= -1.11, indicating well-established in vitro functional evidence supportive of a damaging effect on protein function. Details ▾Hide ▴
Evidence considered
- Mighell et al. 2018 Table S2: L182V Cum_score=-1.238
- High_conf=True
- meeting PS3_Moderate threshold (<= -1.11).
- Direct measurement (not imputed)
- high-confidence flag True.
Sources
vcep_mmc2
PM2 SupportingNM_000314.8:c.544T>G is absent from gnomAD v2.1 and gnomAD v4.1 (0/1,612,242 alleles, AF=0.00000%). Per the PTEN VCEP specification, PM2 is applied at Supporting level for variants with allele frequency <0.00001 (0.001%) in gnomAD. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: 0/1
- 612
- 242 alleles
- AF=0.00000%
- below VCEP PM2_Supporting threshold of <0.001%.
- gnomAD-Canada v1.0: absent.
Sources
PP2 SupportingPTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease (PTEN hamartoma tumor syndrome, autosomal dominant). PP2 is applicable per the PTEN VCEP specification for missense variants in PTEN. Details ▾Hide ▴
Evidence considered
- PTEN has low benign missense variation rate
- missense variants are a known disease mechanism in PHTS.
- PP2 applicable per PTEN VCEP v3.2.0.
Sources
Not met · 16 · evaluated, threshold not reached
PS1 PS1 requires the same amino acid change (L182V) to have been previously established as pathogenic via a different nucleotide change. No alternative nucleotide substitution producing L182V has been identified as pathogenic in ClinVar; the variant is absent from ClinVar entirely. No evidence of a prior established pathogenic L182V from a different codon change is available. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no prior pathogenic L182V from a different nucleotide change identified.
Still missing
- No known pathogenic L182V from an alternative nucleotide change in ClinVar or literature.
Sources
PS2 PS2 requires a proven de novo observation (both maternity and paternity confirmed) in a patient with PHTS and no family history. No de novo data are available; the variant is absent from ClinVar and no publications were identified. Details ▾Hide ▴
Evidence considered
- No de novo observations found. Variant absent from ClinVar. No publications available.
Still missing
- No de novo testing data available for this variant.
PS4 PS4 requires proband counts with phenotype specificity scores. No proband data are available; the variant is absent from ClinVar and no case reports were identified in the literature. Details ▾Hide ▴
Evidence considered
- No proband data available. Variant absent from ClinVar. No publications identified.
Still missing
- No proband counts or phenotype specificity data available for this variant.
PM1 PM1 requires the variant to be located in a PTEN catalytic motif. The PTEN VCEP defines catalytic motifs as the WPD loop (residues 90-94), P-loop (residues 123-130), and TI-loop (residues 166-168) per NP_000305.3. Position 182 lies outside all three catalytic motifs. Additionally, the variant is not in a statistically significant hotspot. Details ▾Hide ▴
Evidence considered
- Position 182 is outside PTEN catalytic motifs: WPD loop (90-94)
- P-loop (123-130)
- TI-loop (166-168).
- Not in a statistically significant mutational hotspot.
Sources
PM5 PM5 requires a different missense change at the same residue (Leu182) to be pathogenic or likely pathogenic, AND the interrogated variant must have a BLOSUM62 score equal to or less than the known variant. L182S (c.545T>C, p.Leu182Ser) is classified as Pathogenic in ClinVar for macrocephaly/autism syndrome. However, the BLOSUM62 score for Leu->Ser is -2, while Leu->Val (L182V) is +1. Since L182V's BLOSUM62 score (+1) is greater than L182S's score (-2), the BLOSUM62 criterion is not satisfied. Details ▾Hide ▴
Evidence considered
- L182S (ClinVar: Pathogenic
- macrocephaly/autism syndrome) is a pathogenic missense at same residue.
- BLOSUM62: Leu->Val = +1
- Leu->Ser = -2. L182V score (+1) is NOT <= L182S score (-2)
- PM5 BLOSUM62 requirement not met.
Sources
vcep_mmc2clinvar ↗
PM6 PM6 requires assumed de novo occurrence in a proband with PHTS and no family history. No de novo data are available; the variant is absent from ClinVar and no publications were identified. Details ▾Hide ▴
Evidence considered
- No de novo observations available. Variant absent from ClinVar. No publications identified.
Still missing
- No de novo testing data available for this variant.
PP1 PP1 requires co-segregation data with at least 3 meioses across affected family members. No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No co-segregation data available.
Still missing
- No family segregation data available for this variant.
PP3 PP3 for missense variants requires REVEL score >0.7 per the PTEN VCEP specification. The REVEL score for L182V is 0.682, which falls below the >0.7 threshold. BayesDel score (0.206) also does not strongly support a deleterious prediction. SpliceAI max delta is 0.00 (no predicted splicing impact). Multiple lines of computational evidence do not support a deleterious effect at the VCEP-defined threshold. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.682 (below VCEP PP3 threshold of >0.7).
- BayesDel score: 0.206 (not strongly deleterious).
- SpliceAI max delta: 0.00 (no splicing impact predicted).
Sources
BA1 BA1 requires gnomAD filtering allele frequency >0.00056 (0.056%) per the PTEN VCEP specification. The variant is absent from gnomAD v2.1 and v4.1 (0/1,612,242 alleles, AF=0.00000%). Frequency does not meet the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 0/1
- 612
- 242 alleles
- AF=0.0%
- below BA1 threshold of >0.056%.
Sources
BS1 BS1 requires gnomAD filtering allele frequency from 0.000043 (0.0043%) to 0.00056 (0.056%) per the PTEN VCEP specification. The variant is absent from gnomAD (AF=0.00000%). Frequency does not meet the BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 0/1
- 612
- 242 alleles
- AF=0.0%
- below BS1 threshold of >=0.0043%.
Sources
BS2 BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations are reported; the variant is absent from gnomAD (0 homozygotes). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 0 homozygotes. No homozygous observations in any population database.
Sources
BS3 BS3_Supporting requires phosphatase activity >0 per Mighell et al. 2018. L182V Cum_score is -1.24, indicating reduced (not normal) phosphatase activity. BS3 is not met. BS3_Strong applies only to intronic/synonymous variants with splicing assays showing no impact and is not applicable to this missense variant. Details ▾Hide ▴
Evidence considered
- Mighell et al. 2018: L182V Cum_score=-1.24
- not >0. BS3_Supporting threshold not met.
- BS3_Strong (splicing assay) not applicable for this missense variant.
Sources
vcep_mmc2
BS4 BS4 requires lack of segregation in affected family members. No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family segregation data available for this variant.
BP2 BP2 requires observation in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis/unknown phase with different P/LP PTEN variants. No such phase data are available. Details ▾Hide ▴
Evidence considered
- No cis/trans phase data available for this variant.
Still missing
- No phase data with other PTEN P/LP variants available.
BP4 BP4 for missense variants requires REVEL score <0.5 per the PTEN VCEP specification. L182V REVEL score is 0.682, which exceeds this threshold. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.682 (above BP4 threshold of <0.5 for missense variants).
Sources
revel
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease, with at least two such cases required per the PTEN VCEP specification. No such cases are available. Details ▾Hide ▴
Evidence considered
- No cases with alternate molecular basis identified.
Still missing
- No cases with an alternate molecular basis for disease identified.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies only to null variants (nonsense, frameshift, canonical splice site, initiation codon, exon deletion). NM_000314.8:c.544T>G is a missense substitution (p.Leu182Val) and does not fall into any PVS1 null-variant bucket per the PTEN VCEP PVS1 decision tree. Details ▾Hide ▴
No further detail was recorded.
PP4 VCEPPP4 is marked Not Applicable by the ClinGen PTEN Expert Panel v3.2.0. Phenotype specificity has been incorporated into PS4 Use 2 rule specifications. Details ▾Hide ▴
Evidence considered
- PTEN VCEP: PP4 Not Applicable
- phenotype specificity incorporated into PS4.
Sources
PP5 VCEPPP5 is marked Not Applicable for this VCEP by the ClinGen PTEN Expert Panel v3.2.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- PTEN VCEP: PP5 Not Applicable for this VCEP per ClinGen SVI VCEP Review Committee.
Sources
BP1 VCEPBP1 is marked Not Applicable by the ClinGen PTEN Expert Panel v3.2.0. This rule is not applicable to PTEN. Details ▾Hide ▴
BP6 VCEPBP6 is marked Not Applicable for this VCEP by the ClinGen PTEN Expert Panel v3.2.0. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- PTEN VCEP: BP6 Not Applicable for this VCEP per ClinGen SVI VCEP Review Committee.
Sources
BP7 N/ABP7 applies to synonymous or intronic variants (at or beyond +7/-21) for which splicing prediction algorithms predict no impact. NM_000314.8:c.544T>G is a missense variant (p.Leu182Val) and does not meet the variant type requirement for BP7. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Leu182Val)
- not synonymous or intronic.
PS5 N/APS5 is not a criterion in the ACMG/AMP 2015 guidelines nor in the ClinGen PTEN Expert Panel specifications v3.2.0. This criterion is not defined for PTEN variant interpretation. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.544T>G
- Protein (HGVS p.)
- NP_000305.3:p.(Leu182Val)
- GRCh38
- chr10:87952169 T>G
- GRCh37
- chr10:89711926 T>G
- COSMIC
- COSV64288496
Gene diagram
Every interpreted variant in PTEN, mapped onto the exon structure of NM_000314.8. Select a row to find it on the plot.
PTENNM_000314.8
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PTEN
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
0 / 1,612,242 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,612,242 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1612242 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74972 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.682
- BayesDel
- 0.206
How the predictions were used
PP3 PP3 for missense variants requires REVEL score >0.7 per the PTEN VCEP specification. The REVEL score for L182V is 0.682, which falls below the >0.7 threshold. BayesDel score (0.206) also does not strongly support a deleterious prediction. SpliceAI max delta is 0.00 (no predicted splicing impact). Multiple lines of computational evidence do not support a deleterious effect at the VCEP-defined threshold. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.682 (below VCEP PP3 threshold of >0.7).
- BayesDel score: 0.206 (not strongly deleterious).
- SpliceAI max delta: 0.00 (no splicing impact predicted).
Sources
BP4 BP4 for missense variants requires REVEL score <0.5 per the PTEN VCEP specification. L182V REVEL score is 0.682, which exceeds this threshold. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.682 (above BP4 threshold of <0.5 for missense variants).
Sources
revel
BP7 N/ABP7 applies to synonymous or intronic variants (at or beyond +7/-21) for which splicing prediction algorithms predict no impact. NM_000314.8:c.544T>G is a missense variant (p.Leu182Val) and does not meet the variant type requirement for BP7. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Leu182Val)
- not synonymous or intronic.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.682. BayesDel score = 0.205836.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
0 / 1,612,242 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637575
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000314.8%3Ac.544T%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89711926-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87952169-T-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-87952169-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.544T…
- OncoKB ↗www.oncokb.org/gene/PTEN/L182V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=139197064
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1612242 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74972 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.682. BayesDel score = 0.205836.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64288496, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.