About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.253+5G>T, p.?
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes), meeting the PTEN VCEP PM2_Supporting threshold of <0.001% (0.00001) allele frequency.
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: PM2 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.910 maximum delta
Recorded SpliceAI maximum delta score: 0.910. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
5 reported laboratory submissions
4 Pathogenic · 1 Likely pathogenic.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV64298366, n = 2 times).
Context only
COSMIC ↗
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: 1 met · 6 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.253+5G>T is an intronic variant at the +5 position of the PTEN donor splice site. This variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).
SpliceAI strongly predicts a deleterious splicing effect (max delta score 0.91; acceptor loss 0.91, donor loss 0.85), consistent with disruption of normal splicing at the exon 4-intron 4 junction.
The PTEN VCEP PVS1 decision tree applies to canonical GT-AG ±1,2 splice site disruptions. c.253+5G>T at the +5 position does not fall within the canonical splice site branch of the decision tree, and PVS1 is not met under the VCEP framework.
This variant is reported in ClinVar (VariationID 427617) as Pathogenic by four clinical laboratories and Likely pathogenic by one, with review status 'criteria provided, single submitter.' No expert panel review is available.
The variant has been observed in somatic cancers (COSMIC COSV64298366, n=2), consistent with a role in tumorigenesis, though somatic observations are not directly applicable to germline ACMG/AMP criteria.
Key functional evidence may exist in PMID:28677221 (Chen et al. 2017), which characterized cryptic splicing in 34 germline PTEN intronic variants from Cowden syndrome patients, but full-text confirmation that c.253+5G>T was specifically studied is unavailable. Until splicing assay data are confirmed, PS3 cannot be applied.
Multiple criteria require additional evidence to be fully assessed: PS3 (RNA/mini-gene splicing assay), PS4 (proband specificity scores), PP3 (VarSeak concordance with SpliceAI), PS1 (comparison to other pathogenic variants at c.253+5), and PP1/BS4 (segregation data).
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes), meeting the PTEN VCEP PM2_Supporting threshold of <0.001% (0.00001) allele frequency. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Meets VCEP PM2_Supporting threshold: allele frequency <0.001%
Sources
Not met · 6 · evaluated, threshold not reached
PVS1 The PTEN VCEP PVS1 decision tree covers canonical GT-AG ±1,2 splice site disruptions that lead to exon skipping or cryptic splice site usage with NMD prediction. c.253+5G>T is at the +5 position of the donor splice site, which is outside the canonical ±1,2 positions evaluated by the decision tree. The variant does not fit any branch of the PTEN-specific PVS1 decision tree (nonsense, frameshift, canonical splice sites, deletions, duplications, or initiation codon). Details ▾Hide ▴
Evidence considered
- PTEN VCEP PVS1 decision tree (PVS1_DecisionTree_PTEN.pdf) applies to canonical GT-AG ±1
- 2 splice sites only
- c.253+5G>T is at position +5
- not a canonical ±1
- 2 splice site
- pvs1_variant_assessment confirms canonical_splice_consensus=false
Sources
BA1 This variant is absent from gnomAD v2.1 and v4.1. The VCEP BA1 threshold is a gnomAD filtering allele frequency >0.00056 (0.056%). An absent variant does not meet this threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- VCEP BA1 threshold: >0.056% — not met
Sources
BS1 This variant is absent from gnomAD v2.1 and v4.1. The VCEP BS1 threshold ranges from 0.0000043 (0.00043%, Supporting) to 0.00056 (0.056%, Strong). An absent variant does not meet either threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1
- VCEP BS1 threshold: ≥0.00043% (Supporting) to ≥0.0043% (Strong) — not met
Sources
BS2 This variant is absent from gnomAD v2.1 and v4.1 with no homozygous observations. The VCEP BS2 rule requires observation in the homozygous state in a healthy or PHTS-unaffected individual. No such observations are available. Details ▾Hide ▴
Evidence considered
- No homozygous observations in gnomAD v2.1 or v4.1
- VCEP BS2 requires homozygous state in healthy/PHTS-unaffected individual
Sources
BS3 The VCEP BS3_Strong rule requires an RNA, mini-gene, or other splicing assay demonstrating no splicing impact. No such evidence is available for this variant. The mmc2.xlsx phosphatase activity dataset (Mighell et al. 2018, PMID:29706350) applies only to missense variants and does not provide evidence for this intronic variant. In the absence of experimental data showing no splicing impact, BS3 cannot be applied. Details ▾Hide ▴
Evidence considered
- No RNA/mini-gene assay demonstrating no splicing impact identified
- mmc2.xlsx (Mighell et al. 2018) is missense-only
- not applicable to intronic c.253+5G>T
- SpliceAI predicts splicing impact (delta 0.91)
- inconsistent with BS3 assertion of no impact
Still missing
- No experimental data demonstrating no splicing impact for this variant
Sources
cspec ↗vcep_mmc2
BP4 The VCEP BP4 rule for splicing variants requires SpliceAI scores in the 0-0.2 range (concordant with VarSeak Class 1-2) indicating no splicing impact. SpliceAI predicts a deleterious splicing impact for this variant with a max delta score of 0.91 (acceptor loss 0.91), well above the benign threshold. BP4 requires prediction of no impact, which is contradicted by the available in silico evidence. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.91 (acceptor_loss = 0.91)
- well above the 0.2 benign threshold
- VCEP BP4 requires SpliceAI 0-0.2 for benign splicing prediction
Sources
Not assessed · 10 · no assessment recorded
PS1 The VCEP PS1 rule allows application when a different variant at the same nucleotide position is a known pathogenic splicing variant with equal or greater predicted impact. Data on other variants at the c.253+5 position (e.g., c.253+5G>A or c.253+5G>C) and their SpliceAI predictions were not available for comparison. Details ▾Hide ▴
Evidence considered
- VCEP PS1 rule: same nucleotide position as known pathogenic splicing variant with equal or greater predicted impact
Still missing
- No data on pathogenic variants at c.253+5 nucleotide position for comparison of in silico splicing predictions
Sources
PS2 No de novo observations for this variant were identified in the literature or ClinVar submissions. De novo data are required to apply PS2 under the VCEP framework. Details ▾Hide ▴
PS3 The VCEP PS3_Strong rule can be applied when an RNA, mini-gene, or other assay demonstrates impact on splicing. PMID:28677221 (Chen et al. 2017) is a study of cryptic splicing in 34 germline PTEN intronic variants from Cowden syndrome patients and likely contains relevant functional data, but the full text is unavailable for confirmation that c.253+5G>T was specifically studied. The mmc2.xlsx phosphatase activity dataset applies only to missense variants and is not relevant to this intronic variant. Details ▾Hide ▴
Evidence considered
- PMID:28677221 (Chen et al. 2017) title and abstract describe characterization of cryptic splicing in PTEN intronic variants in Cowden syndrome — highly relevant but full text unavailable for variant confirmation
- mmc2.xlsx (Mighell et al. 2018) phosphatase assay is missense-only
- not applicable to intronic variant
Still missing
- Full text of PMID:28677221 unavailable
- likely contains splicing assay data for this variant
- No other RNA/mini-gene splicing assay data identified
Sources
PS4 The VCEP PS4 rule requires probands with specificity scores. ClinVar reports this variant as Pathogenic by 4 clinical laboratories and Likely pathogenic by 1, with review status 'criteria provided, single submitter.' However, no proband counts with phenotype specificity scores are available for formal PS4 assessment. The variant is absent from gnomAD, consistent with rarity in the general population. Details ▾Hide ▴
Evidence considered
- ClinVar: Pathogenic (4 labs)
- Likely pathogenic (1 lab)
- review status: criteria provided
- single submitter
- Absent from gnomAD v2.1 and v4.1
Still missing
- No proband counts with phenotype specificity scores available
- No expert panel review in ClinVar
Sources
PM6 No de novo observations for this variant were identified. The VCEP PM6 rule requires one or more de novo observations depending on confirmation status and strength level. Details ▾Hide ▴
PP1 No co-segregation data are available for this variant. The VCEP PP1 rule requires co-segregation with disease in multiple affected family members with specific meioses counts for each strength level. Details ▾Hide ▴
PP3 SpliceAI predicts a deleterious splicing impact for this variant (max delta score 0.91; acceptor loss delta 0.91, donor loss delta 0.85), well above the >0.2 threshold. However, the VCEP PP3 rule for splicing variants requires concordance of both SpliceAI and VarSeak. VarSeak data are not available, so the required concordance cannot be confirmed. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.91 (acceptor_loss = 0.91
- donor_loss = 0.85)
- SpliceAI >0.2 threshold met for predicted deleterious splicing impact
- VarSeak data unavailable for required VCEP concordance assessment
Still missing
- VarSeak score unavailable
- VCEP PP3 requires concordance of SpliceAI and VarSeak for splicing variants
Sources
BS4 No segregation data are available for this variant. The VCEP BS4 rule requires lack of segregation in affected members of one family (Supporting) or two or more families (Strong). Details ▾Hide ▴
BP2 No co-occurrence or phase data are available for this variant. The VCEP BP2 rule requires observation in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis/phase unknown with different pathogenic/likely pathogenic PTEN variants. Details ▾Hide ▴
BP5 The VCEP BP5 rule requires the variant to be found in a case with an alternate molecular basis for disease (at least two such cases, with the other gene/disorder being highly penetrant and no phenotypic overlap with PTEN). No such cases have been identified for this variant. Details ▾Hide ▴
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PM1 N/AThe VCEP PM1 rule is limited to residues within the PTEN catalytic motifs (NP_000305.3 residues 90-94, 123-130, 166-168). c.253+5G>T is an intronic variant at the +5 position of intron 4 and does not alter a catalytic motif residue. Details ▾Hide ▴
Evidence considered
- VCEP PM1 defined catalytic motifs: residues 90-94
- 123-130
- 166-168 (NP_000305.3)
- c.253+5 is intronic
- upstream of any catalytic motif residue
Sources
PM5 N/APM5 requires a missense change at an amino acid residue where a different pathogenic missense change has been observed. c.253+5G>T is an intronic (splice site) variant, not a missense variant, and the variant does not encode an amino acid change (NP_000305.3:p.?). Details ▾Hide ▴
Evidence considered
- Variant class is not missense-like
- PM5 is specific to missense variants at the same residue
- pm5_candidates.json confirms not eligible for classic same-residue missense PM5 search
Sources
cspec ↗pm5_candidates
PP2 N/APP2 is specific to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. c.253+5G>T is an intronic splice site variant, not a missense variant. Details ▾Hide ▴
Evidence considered
- VCEP PP2 rule text: 'Missense variant in a gene that has a low rate of benign missense variation'
- c.253+5G>T is intronic
- not missense
Sources
PP4 VCEPThe PTEN VCEP v3.2.0 declares PP4 'Not Applicable.' Phenotype specificity has been incorporated into the rule specifications for PS4 Use 2. Details ▾Hide ▴
Evidence considered
- PTEN VCEP v3.2.0: PP4 not applicable
- phenotype specificity incorporated into PS4 rules
Sources
PP5 VCEPThe PTEN VCEP v3.2.0 declares PP5 'Not Applicable for this VCEP.' This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- PTEN VCEP v3.2.0: PP5 not for use per ClinGen SVI VCEP Review Committee recommendation
Sources
BP1 VCEPThe PTEN VCEP v3.2.0 declares BP1 'Not Applicable.' Details ▾Hide ▴
BP6 VCEPThe PTEN VCEP v3.2.0 declares BP6 'Not Applicable for this VCEP.' This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Evidence considered
- PTEN VCEP v3.2.0: BP6 not for use per ClinGen SVI VCEP Review Committee recommendation
Sources
BP7 N/AThe VCEP BP7 rule applies to intronic variants 'at or beyond +7/-21.' c.253+5G>T is at the +5 position of the donor splice site, which is within the splice consensus region (+3 to +6) and does not meet the positional requirement of 'at or beyond +7.' Additionally, SpliceAI predicts splicing impact (delta 0.91), which would contradict the BP7 requirement that splicing prediction algorithms predict no impact. Details ▾Hide ▴
Evidence considered
- c.253+5G>T is at position +5
- within the splice donor consensus and not at or beyond +7 as required by VCEP BP7
- SpliceAI predicts splicing impact (delta 0.91)
- inconsistent with 'predict no impact' requirement
Sources
PS5 N/APP5 is declared 'Not Applicable for this VCEP' by the ClinGen PTEN Expert Panel v3.2.0. PS5 as the stronger form of PP5 is similarly not applicable under this VCEP framework. Details ▾Hide ▴
Evidence considered
- PTEN VCEP v3.2.0: PP5/PS5 not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.253+5G>T
- Protein (HGVS p.)
- NP_000305.3:p.?
- GRCh38
- chr10:87931094 G>T
- GRCh37
- chr10:89690851 G>T
- ClinVar
- 427617, 427618
- COSMIC
- COSV64298366
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
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 The VCEP BP4 rule for splicing variants requires SpliceAI scores in the 0-0.2 range (concordant with VarSeak Class 1-2) indicating no splicing impact. SpliceAI predicts a deleterious splicing impact for this variant with a max delta score of 0.91 (acceptor loss 0.91), well above the benign threshold. BP4 requires prediction of no impact, which is contradicted by the available in silico evidence. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.91 (acceptor_loss = 0.91)
- well above the 0.2 benign threshold
- VCEP BP4 requires SpliceAI 0-0.2 for benign splicing prediction
Sources
PP3 SpliceAI predicts a deleterious splicing impact for this variant (max delta score 0.91; acceptor loss delta 0.91, donor loss delta 0.85), well above the >0.2 threshold. However, the VCEP PP3 rule for splicing variants requires concordance of both SpliceAI and VarSeak. VarSeak data are not available, so the required concordance cannot be confirmed. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.91 (acceptor_loss = 0.91
- donor_loss = 0.85)
- SpliceAI >0.2 threshold met for predicted deleterious splicing impact
- VarSeak data unavailable for required VCEP concordance assessment
Still missing
- VarSeak score unavailable
- VCEP PP3 requires concordance of SpliceAI and VarSeak for splicing variants
Sources
BP7 N/AThe VCEP BP7 rule applies to intronic variants 'at or beyond +7/-21.' c.253+5G>T is at the +5 position of the donor splice site, which is within the splice consensus region (+3 to +6) and does not meet the positional requirement of 'at or beyond +7.' Additionally, SpliceAI predicts splicing impact (delta 0.91), which would contradict the BP7 requirement that splicing prediction algorithms predict no impact. Details ▾Hide ▴
Evidence considered
- c.253+5G>T is at position +5
- within the splice donor consensus and not at or beyond +7 as required by VCEP BP7
- SpliceAI predicts splicing impact (delta 0.91)
- inconsistent with 'predict no impact' requirement
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.91).
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 17576681 ↗Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.Buratti E et al. · 2007No paper-specific finding is recorded.
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PMID 25645574 ↗ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.No paper-specific finding is recorded.
-
PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
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PMID 28677221 ↗Characterization of cryptic splicing in germline PTEN intronic variants in Cowden syndrome.Chen HJ et al. · 2017No paper-specific finding is recorded.
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PMID 9536098 ↗Statistical features of human exons and their flanking regions.Zhang MQ · 1998No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.No paper-specific finding is recorded.
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PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007No paper-specific finding is recorded.
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PMID 20301661 ↗PTEN Hamartoma Tumor Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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
Recorded maximum delta 0.910
Open source ↗
ClinVar
4 Pathogenic · 1 Likely pathogenic
Open source ↗
COSMIC
Captured COSMIC 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/427617/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89690851-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87931094-G-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.253%…
- OncoKB ↗www.oncokb.org/gene/PTEN/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=139206530
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 Pathogenic (4 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 427617)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.91).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV64298366, n = 2 times).