About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.634+1G>C, p.?
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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
PVS1Very strong
PVS1 · very strong
NM_000314.8:c.634+1G>C disrupts the canonical +1 donor site of intron 6 in the biologically relevant transcript NM_000314.8. The PTEN-specific PVS1 decision tree indicates that canonical GT-AG splice-site disruption at or 5' to c.1121 (p.D375) is assigned PVS1; this variant is upstream of that threshold and is therefore consistent with PTEN loss of function under the PTEN VCEP rule.
PM2Supporting
PM2 · supporting
The variant is absent from both gnomAD v2.1 and gnomAD v4.1, satisfying the PTEN PM2_Supporting population rarity rule.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
PTEN CSPEC/VCEP final-classification framework from final_classification_framework.json (criteria-combination rules; Richards et al. 2015 combining rules as implemented in the CSPEC ruleset).
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 ↗
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
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 · 3 not met · 12 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The PTEN c.634+1G>C (p.?) variant has been observed in somatic cancers in COSMIC (COSV64295775; 2 occurrences) and has been reported in ClinVar as pathogenic by three clinical laboratories.
This variant is absent from gnomAD v2.1 and gnomAD v4.1.
In silico splicing analysis predicts a marked effect on RNA processing, with a SpliceAI maximum delta score of 0.99, consistent with disruption of the canonical donor site.
No criteria match.
Met · 2
PVS1 Very strongNM_000314.8:c.634+1G>C disrupts the canonical +1 donor site of intron 6 in the biologically relevant transcript NM_000314.8. The PTEN-specific PVS1 decision tree indicates that canonical GT-AG splice-site disruption at or 5' to c.1121 (p.D375) is assigned PVS1; this variant is upstream of that threshold and is therefore consistent with PTEN loss of function under the PTEN VCEP rule. Details ▾Hide ▴
Rule
PTEN EP PVS1 decision tree: canonical GT-AG splice-site disruption at or 5' to c.1121 in NM_000314.8 => PVS1
Evidence considered
- PTEN VCEP PVS1 decision tree for NM_000314.8
- Variant location at c.634+1 canonical donor site
- VariantValidator exon context showing intron 6 splice-site position
Sources
PM2 SupportingThe variant is absent from both gnomAD v2.1 and gnomAD v4.1, satisfying the PTEN PM2_Supporting population rarity rule. Details ▾Hide ▴
Rule
PTEN EP PM2_Supporting: absent or below 0.001% in gnomAD or another large sequenced population
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- PTEN-specific PM2 threshold
Sources
Not met · 3 · evaluated, threshold not reached
BA1 The variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the PTEN BA1 frequency threshold. Details ▾Hide ▴
Rule
PTEN EP BA1 requires filtering allele frequency >0.056%
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS1 The variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet PTEN BS1 or BS1_Supporting allele-frequency thresholds. Details ▾Hide ▴
Rule
PTEN EP BS1 requires allele frequency >=0.00043% for supporting or >=0.0043% for strong
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BP4 Benign computational evidence was not observed. SpliceAI predicts a strong splice effect with a maximum delta score of 0.99, which argues against BP4. Details ▾Hide ▴
Rule
PTEN EP BP4 for splicing variants requires concordant prediction of no splicing impact by SpliceAI and VarSeak
Evidence considered
- SpliceAI max delta score 0.99
- PTEN-specific BP4 computational rule
Still missing
- No VarSeak output documenting concordant benign prediction
Sources
Not assessed · 12 · no assessment recorded
PS1 PTEN permits PS1 for a different variant at the same nucleotide position as a known pathogenic splicing variant if in silico impact is equal to or greater than the known pathogenic variant, but no same-position comparator variant with the necessary side-by-side evidence was documented. Details ▾Hide ▴
Rule
PTEN EP PS1 requires same amino acid change as a known pathogenic variant or a different variant at the same nucleotide position as a pathogenic splicing variant with equal or greater predicted splice impact
Evidence considered
- PTEN-specific PS1 rule
- ClinVar record present for the queried variant only
Still missing
- No established pathogenic same-position comparator variant was extracted
- No comparative in silico assessment against a known pathogenic same-position splice variant was documented
Sources
PS2 No confirmed de novo occurrence with maternity and paternity established was documented. Details ▾Hide ▴
PS3 PTEN allows PS3 for RNA, minigene, or other assays showing splicing impact, but no directly extracted assay result for NM_000314.8:c.634+1G>C was documented here. The local PTEN functional spreadsheet is a missense phosphatase assay resource and is not applicable to this splice donor variant. Details ▾Hide ▴
Rule
PTEN EP PS3 may be applied when RNA, minigene, or another assay demonstrates splicing impact
Evidence considered
- PTEN-specific PS3 rule
- PTEN VCEP local guidance that mmc2.xlsx is for missense variants
Still missing
- No directly extracted RNA or minigene assay result for this variant
- No case-specific functional summary confirming abnormal splicing was provided
Sources
PS4 The variant is present in ClinVar and reported in COSMIC, but no proband specificity scoring, case-count synthesis, or case-control analysis meeting PTEN PS4 thresholds was documented. Details ▾Hide ▴
Rule
PTEN EP PS4 requires phenotype-specific proband scoring or significant enrichment in affected individuals
Evidence considered
- PTEN-specific PS4 rule
- ClinVar pathogenic submissions
- COSMIC somatic count of 2
Still missing
- No PTEN specificity score calculation
- No curated proband count with phenotypic specificity
- No qualifying case-control enrichment analysis
Sources
PM6 No presumed de novo occurrences in affected individuals without family history were documented. Details ▾Hide ▴
PP1 No segregation data with informative meioses were documented. Details ▾Hide ▴
Rule
PTEN EP PP1 requires 3-4 informative meioses for supporting strength, 5-6 for moderate, and >=7 across at least two families for strong
Evidence considered
- PTEN-specific PP1 rule
Still missing
- No family segregation data
- No count of informative meioses
Sources
PP3 SpliceAI predicts a strong splice effect with a maximum delta score of 0.99, but the PTEN PP3 rule for splicing variants requires concordance of SpliceAI and VarSeak. VarSeak output was not documented, so PP3 was not applied in this pass. Details ▾Hide ▴
Rule
PTEN EP PP3 for splicing variants requires concordance of SpliceAI and VarSeak
Evidence considered
- SpliceAI max delta score 0.99
- PTEN-specific PP3 computational rule
Still missing
- No VarSeak prediction documented for concordance
- No explicit PTEN VCEP-compatible computational concordance statement
Sources
BS2 No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were documented. Details ▾Hide ▴
Rule
PTEN EP BS2 requires homozygous observation in a healthy or PHTS-unaffected individual
Evidence considered
- PTEN-specific BS2 rule
- Population databases show no variant observations
Still missing
- No homozygous observations with unaffected status
Sources
BS3 No RNA, minigene, or other functional study demonstrating no splicing impact for this canonical splice donor variant was documented. Details ▾Hide ▴
Rule
PTEN EP BS3 for intronic/synonymous variants requires RNA, minigene, or other assay showing no splicing impact
Evidence considered
- PTEN-specific BS3 rule
- Local PTEN missense assay resource not applicable to this splice variant
Still missing
- No benign splicing assay result for this variant
Sources
BS4 No nonsegregation data in one or more families were documented. Details ▾Hide ▴
Rule
PTEN EP BS4 requires lack of segregation in one family for supporting or two or more families for strong
Evidence considered
- PTEN-specific BS4 rule
Still missing
- No family nonsegregation evidence
Sources
BP2 No phase data with other pathogenic or likely pathogenic PTEN variants were documented. Details ▾Hide ▴
Rule
PTEN EP BP2 requires observation in trans with a pathogenic/likely pathogenic PTEN variant or at least three cis/phase-unknown observations with different pathogenic PTEN variants
Evidence considered
- PTEN-specific BP2 rule
Still missing
- No cis/trans observations with another pathogenic PTEN variant
Sources
BP5 No evidence was documented showing that affected individuals carrying this variant had an alternate highly penetrant molecular diagnosis with nonoverlapping phenotype. Details ▾Hide ▴
Rule
PTEN EP BP5 requires at least two cases with another highly penetrant molecular basis and no phenotype overlap with PTEN
Evidence considered
- PTEN-specific BP5 rule
Still missing
- No qualifying alternate molecular diagnosis data
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PM1 N/APM1 is specified for residues within PTEN catalytic motifs and mutational hotspot/domain contexts. This variant is a canonical splice donor variant rather than a coding residue change within the defined catalytic motifs. Details ▾Hide ▴
Rule
PTEN EP PM1 applies to residues in catalytic motifs 90-94, 123-130, and 166-168
Evidence considered
- PTEN-specific PM1 rule
- Variant is intronic splice donor
Sources
PM3 N/APM3 is not for use in this PTEN VCEP specification. Details ▾Hide ▴
PM4 N/APM4 is specified for in-frame insertions/deletions or stop-loss variants causing protein length change and does not fit a canonical splice donor substitution. Details ▾Hide ▴
Rule
PTEN EP PM4 applies to in-frame indels affecting relevant motifs or protein extension variants
Evidence considered
- PTEN-specific PM4 rule
- Variant type is canonical splice donor SNV
Sources
PM5 N/APM5 is a missense residue-based rule and does not apply to this canonical splice donor variant. Details ▾Hide ▴
Rule
PTEN EP PM5 applies to a missense change at a residue with a different pathogenic missense change
Evidence considered
- PTEN-specific PM5 rule
- Variant is not missense
Sources
PP2 N/APP2 is a missense-specific rule and does not apply to a canonical splice donor variant. Details ▾Hide ▴
Rule
PTEN EP PP2 applies to missense variants
Evidence considered
- PTEN-specific PP2 rule
- Variant is not missense
Sources
PP4 N/APP4 is designated not applicable by the PTEN VCEP because phenotype specificity is incorporated into PS4 specifications. Details ▾Hide ▴
PP5 N/APP5 is not for use in this PTEN VCEP specification. Details ▾Hide ▴
BP1 N/ABP1 is designated not applicable by the PTEN VCEP. Details ▾Hide ▴
BP3 N/ABP3 is designated not applicable by the PTEN VCEP. Details ▾Hide ▴
BP6 N/ABP6 is not for use in this PTEN VCEP specification. Details ▾Hide ▴
BP7 N/ABP7 is specified for synonymous variants or intronic variants at or beyond +7/-21 with no predicted splice effect. This variant is a canonical +1 splice donor substitution, so BP7 does not apply. Details ▾Hide ▴
Rule
PTEN EP BP7 applies only to synonymous or deep intronic variants at or beyond +7/-21 with no predicted splice impact
Evidence considered
- PTEN-specific BP7 rule
- Variant position c.634+1
- SpliceAI predicts splice impact
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.634+1G>C
- Protein (HGVS p.)
- NP_000305.3:p.?
- GRCh38
- chr10:87952260 G>C
- GRCh37
- chr10:89712017 G>C
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
BP4 Benign computational evidence was not observed. SpliceAI predicts a strong splice effect with a maximum delta score of 0.99, which argues against BP4. Details ▾Hide ▴
Rule
PTEN EP BP4 for splicing variants requires concordant prediction of no splicing impact by SpliceAI and VarSeak
Evidence considered
- SpliceAI max delta score 0.99
- PTEN-specific BP4 computational rule
Still missing
- No VarSeak output documenting concordant benign prediction
Sources
PP3 SpliceAI predicts a strong splice effect with a maximum delta score of 0.99, but the PTEN PP3 rule for splicing variants requires concordance of SpliceAI and VarSeak. VarSeak output was not documented, so PP3 was not applied in this pass. Details ▾Hide ▴
Rule
PTEN EP PP3 for splicing variants requires concordance of SpliceAI and VarSeak
Evidence considered
- SpliceAI max delta score 0.99
- PTEN-specific PP3 computational rule
Still missing
- No VarSeak prediction documented for concordance
- No explicit PTEN VCEP-compatible computational concordance statement
Sources
BP7 N/ABP7 is specified for synonymous variants or intronic variants at or beyond +7/-21 with no predicted splice effect. This variant is a canonical +1 splice donor substitution, so BP7 does not apply. Details ▾Hide ▴
Rule
PTEN EP BP7 applies only to synonymous or deep intronic variants at or beyond +7/-21 with no predicted splice impact
Evidence considered
- PTEN-specific BP7 rule
- Variant position c.634+1
- SpliceAI predicts splice impact
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99).
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
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/427620/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89712017-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87952260-G-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.634%…
- OncoKB ↗www.oncokb.org/gene/PTEN
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 (3 clinical laboratories).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV64295775, n = 2 times).