About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.745G>A, p.(Val249Met)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the PTEN EP PM2 threshold of <0.00001 (0.001%) for population data and supports PM2_Supporting.
PP2Supporting
PP2 · supporting
This is a PTEN missense variant, and the PTEN Expert Panel retains PP2 for missense changes in a gene where missense variation is a recognized disease mechanism.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ACMG/AMP classification using ClinGen PTEN Expert Panel Specifications v3.2.0
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PTEN VCEP v3.2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 7 not met · 10 not assessed · 9 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.745G>A (NP_000305.3:p.(Val249Met), p.(V249M)) is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN Expert Panel PM2 threshold of <0.00001 (0.001%) and supports PM2_Supporting.
As a PTEN missense variant, p.(Val249Met) supports PP2 because missense variation is an established disease mechanism for this gene in the PTEN Expert Panel framework.
In the Mighell PTEN phosphatase assay, p.Val249Met has a cumulative score of -0.30689816, which is above the PS3_Moderate threshold of <= -1.11 and below the BS3 threshold of >0, so the available PTEN-specific functional data do not support either PS3 or BS3.
The REVEL score is 0.679, which is below the PTEN PP3 threshold of >0.7 and above the PTEN BP4 threshold of <0.5, so computational missense evidence does not support either criterion.
With PM2_Supporting and PP2 met, and no additional PTEN Expert Panel pathogenic or benign criteria satisfied, PTEN p.(Val249Met) is classified as a variant of uncertain significance.
No criteria match.
Met · 2
PM2 SupportingThe variant is absent from gnomAD v2.1 and absent from gnomAD v4.1, which is below the PTEN EP PM2 threshold of <0.00001 (0.001%) for population data and supports PM2_Supporting. Details ▾Hide ▴
Rule
PM2_Supporting when allele frequency is <0.00001 in gnomAD; if multiple alleles are present within any subpopulation, subpopulation AF must be <0.00002.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
Sources
PP2 SupportingThis is a PTEN missense variant, and the PTEN Expert Panel retains PP2 for missense changes in a gene where missense variation is a recognized disease mechanism. Details ▾Hide ▴
Rule
Missense variant in a gene with low benign missense variation and where missense variants are a common disease mechanism.
Evidence considered
- Missense consequence p.(Val249Met)
Sources
Not met · 7 · evaluated, threshold not reached
PS3 In PTEN supplementary Table S2 from Mighell et al., p.Val249Met (V249M) has Cum_score -0.30689816, which is above the PTEN EP PS3_Moderate threshold of <= -1.11; no splicing assay showing damaging impact was provided. Details ▾Hide ▴
Rule
PS3_Moderate for phosphatase activity <= -1.11 per Mighell et al. 2018.
Evidence considered
- V249M
- Cum_score=-0.30689816
- High_conf=True
Sources
PM1 PTEN PM1 is restricted to catalytic motif residues 90-94, 123-130, and 166-168; Val249 lies outside these defined motifs. Details ▾Hide ▴
Rule
Located in PTEN catalytic motifs 90-94, 123-130, or 166-168.
Evidence considered
- Residue 249
Sources
PP3 For PTEN missense variants, PP3 requires REVEL >0.7; the assembled REVEL score is 0.679, so this threshold is not reached. Details ▾Hide ▴
Rule
PP3 for PTEN missense variants requires REVEL >0.7.
Evidence considered
- REVEL=0.679
Sources
BA1 BA1 requires gnomAD filtering allele frequency >0.00056 (0.056%); this variant is absent from gnomAD v2.1 and v4.1. Details ▾Hide ▴
Rule
BA1 for PTEN requires gnomAD filtering AF >0.00056.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
Sources
BS1 BS1 requires a gnomAD filtering allele frequency from 0.000043 to 0.00056 for strong strength or from 0.0000043 to 0.000043 for supporting strength; this variant is absent from gnomAD v2.1 and v4.1. Details ▾Hide ▴
Rule
BS1 thresholds are 0.000043-0.00056 (strong) or 0.0000043-0.000043 (supporting).
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
Sources
BS3 In the PTEN Mighell assay, BS3_Supporting requires phosphatase activity >0; p.Val249Met has Cum_score -0.30689816, so it does not meet the benign functional threshold, and no splicing assay showing no effect was provided. Details ▾Hide ▴
Rule
BS3_Supporting for PTEN missense variants requires phosphatase activity >0 per Mighell et al. 2018.
Evidence considered
- V249M
- Cum_score=-0.30689816
- High_conf=True
Sources
BP4 For PTEN missense variants, BP4 requires REVEL <0.5; the assembled REVEL score is 0.679, so the benign computational threshold is not met. Details ▾Hide ▴
Rule
BP4 for PTEN missense variants requires REVEL <0.5.
Evidence considered
- REVEL=0.679
Sources
Not assessed · 10 · no assessment recorded
PS1 No workspace evidence established a previously classified pathogenic PTEN variant producing the same amino-acid change p.Val249Met. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant.
Still missing
- Variant-level same-amino-acid comparison against curated PTEN pathogenic variants was not provided in the workspace.
PS2 No confirmed de novo data were provided. Details ▾Hide ▴
Rule
Confirmed de novo occurrence in an affected individual with no family history.
Still missing
- Proband phenotype, parental testing, and family history were not available.
PS4 The workspace did not provide qualifying PTEN phenotype-specific proband counts, specificity scores, or case-control enrichment data for this variant. Details ▾Hide ▴
Rule
Requires PTEN phenotype-specific proband specificity score or significant case-control enrichment.
Evidence considered
- Literature PS4 screen had no passing items
- ClinVar classification: Uncertain significance
Still missing
- No usable PTEN phenotype-specific case evidence or case-control data for NM_000314.8:c.745G>A were assembled.
Sources
PM5 No curated evidence in the workspace established a different pathogenic or likely pathogenic missense change at PTEN codon 249 with a qualifying BLOSUM62 comparison. Details ▾Hide ▴
Rule
Different pathogenic/likely pathogenic missense change at same residue with equal or more severe BLOSUM62 score.
Still missing
- Codon-specific pathogenic comparison set was not assembled.
Sources
PM6 No assumed de novo observations were provided. Details ▾Hide ▴
Rule
Assumed de novo occurrence with appropriate PTEN phenotype context.
Still missing
- Case-level parental testing and family history were not available.
Sources
PP1 No segregation data were provided to count informative meioses. Details ▾Hide ▴
Rule
Requires 3-4, 5-6, or >=7 informative meioses for supporting, moderate, or strong strength, respectively.
Still missing
- Family segregation information was not available.
Sources
BS2 No homozygous observations in healthy or PHTS-unaffected individuals were provided. Details ▾Hide ▴
Rule
Requires homozygous observation in healthy/PHTS-unaffected individual(s).
Still missing
- Healthy homozygote data were not available.
Sources
BS4 No lack-of-segregation evidence was provided. Details ▾Hide ▴
Rule
Requires lack of segregation in one family (supporting) or two or more families (strong).
Still missing
- Family segregation data were not available.
Sources
BP2 No phase data with a pathogenic or likely pathogenic PTEN variant were provided. Details ▾Hide ▴
Rule
Observed in trans with a pathogenic/likely pathogenic PTEN variant or >=3 cis/phase-unknown observations with different pathogenic/likely pathogenic PTEN variants.
Still missing
- Cis/trans data with another pathogenic PTEN variant were not available.
Sources
BP5 No evidence of an alternate highly penetrant molecular diagnosis with non-overlapping PTEN phenotype was provided. Details ▾Hide ▴
Rule
Requires alternate highly penetrant molecular diagnosis with no phenotype overlap and at least two such cases.
Still missing
- Case-level alternate molecular diagnosis data were not available.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APTEN-specific PVS1 applies to null variants and canonical splice-disrupting events; NM_000314.8:c.745G>A is a missense substitution, p.(Val249Met). Details ▾Hide ▴
Rule
Use PTEN PVS1 decision tree for null/splice-disrupting variants only.
Evidence considered
- NM_000314.8:c.745G>A
- NP_000305.3:p.(Val249Met)
Sources
cspec ↗vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
PM3 N/APM3 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
PM4 N/APM4 applies to in-frame insertions/deletions or stop-loss variants; this variant is a missense substitution. Details ▾Hide ▴
Rule
Protein length change due to in-frame indel or stop-loss.
Evidence considered
- Missense variant p.(Val249Met)
Sources
PP4 N/APP4 is not applicable in the PTEN Expert Panel specification because phenotype specificity is incorporated into PS4. Details ▾Hide ▴
PP5 N/APP5 is not applicable in the current ClinGen framework. Details ▾Hide ▴
BP1 N/ABP1 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
BP6 N/ABP6 is not applicable in the current ClinGen framework. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or qualifying intronic variants; NM_000314.8:c.745G>A is a missense variant. Details ▾Hide ▴
Rule
BP7 is restricted to synonymous or intronic variants at/beyond +7/-21 with no predicted splice impact.
Evidence considered
- Missense consequence p.(Val249Met)
- SpliceAI max delta=0.04
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.745G>A
- Protein (HGVS p.)
- NP_000305.3:p.(Val249Met)
- GRCh38
- chr10:87957963 G>A
- GRCh37
- chr10:89717720 G>A
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 For PTEN missense variants, PP3 requires REVEL >0.7; the assembled REVEL score is 0.679, so this threshold is not reached. Details ▾Hide ▴
Rule
PP3 for PTEN missense variants requires REVEL >0.7.
Evidence considered
- REVEL=0.679
Sources
BP4 For PTEN missense variants, BP4 requires REVEL <0.5; the assembled REVEL score is 0.679, so the benign computational threshold is not met. Details ▾Hide ▴
Rule
BP4 for PTEN missense variants requires REVEL <0.5.
Evidence considered
- REVEL=0.679
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants; NM_000314.8:c.745G>A is a missense variant. Details ▾Hide ▴
Rule
BP7 is restricted to synonymous or intronic variants at/beyond +7/-21 with no predicted splice impact.
Evidence considered
- Missense consequence p.(Val249Met)
- SpliceAI max delta=0.04
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Cancer hotspots
Captured Cancer Hotspots source record
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/variation/1378842/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89717720-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87957963-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.745G…
- OncoKB ↗www.oncokb.org/gene/PTEN/V249M
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV64304069, n = 1 times).