Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
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.
About PTEN
PTEN is a tumor suppressor gene that encodes a phosphatase converting the lipid messenger PIP3 back to PIP2 at the cell membrane, thereby restraining the AKT/mTOR signaling pathway that drives cell growth, proliferation, and survival. It is one of the most frequently mutated genes across many types of human cancer, and its loss promotes unchecked cell growth, survival, and genomic instability, partly through impaired DNA repair. Germline loss-of-function variants in PTEN cause Cowden syndrome, an inherited cancer predisposition disorder associated with elevated risk of breast and thyroid cancer.
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. 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.
Met (Moderate): Mighell 2018 saturation mutagenesis measured a phosphatase activity score of -3.483, well below the -1.11 pathogenic threshold.
PM2Supporting
PM2 · supporting
Met (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the <0.001% population-absence threshold.
PP3Supporting
PP3 · supporting
Met (Supporting): REVEL score 0.967 exceeds the VCEP's >0.7 pathogenic-supporting threshold for missense variants.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Applied ClinGen PTEN VCEP (CSPEC v3.2) criteria PS3 (Moderate), PM2 (Supporting), and PP3 (Supporting); with no combination rule met, the variant defaults to VUS.
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.
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.
ACMG/AMP criteria under ClinGen PTEN VCEP v3.2, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 4 not met · 13 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Variant NM_000314.6:c.95T>G (NP_000305.3:p.(Ile32Ser)) is a missense substitution, not a null (nonsense/frameshift/canonical splice/CNV) variant and not an in-frame indel or stop-loss/extension event.
PVS1 requires the PTEN VCEP null-variant decision tree (nonsense, frameshift, canonical GT-AG splice disruption, or CNV) with NMD/p.D375 positional logic; a missense change is out of scope, so PVS1 is not_applicable.
PM4 requires an in-frame indel (non-repeat region or catalytic motif) or a stop-loss/extension; a single-residue missense substitution produces no protein length change, so PM4 is not_applicable.
BP3 is explicitly designated Not Applicable in the PTEN CSPEC v3.2 and, independently, has no repeat-region in-frame indel event to evaluate for this missense variant.
PTEN VCEP-specific functional assay data (Mighell et al. 2018 saturation mutagenesis, PMID 29706350, Table S2 of mmc2.xlsx) provides a directly measured, high-confidence, quality-filter-passing phosphatase activity score (Cum_score = -3.483) for NP_000305.3:p.(I32S) that meets the VCEP PS3_Moderate threshold (<= -1.11) and is inconsistent with the BS3 threshold (>0).
PM3 is not applicable under the PTEN Expert Panel framework.
BP2 cannot be assessed because qualifying phase and allelic co-occurrence observations are not documented in the case-evidence bundle.
Variant NM_000314.6:c.95T>G / p.(Ile32Ser) is missense, so the missense in-silico sub-path (REVEL) governs PP3/BP4 per the PTEN VCEP CSPEC v3.2, not the splicing sub-path (SpliceAI/VarSeak), which the VCEP explicitly restricts to synonymous/intronic variants.
Local REVEL score = 0.967, exceeding the VCEP PP3 threshold of >0.7, so PP3 is applied at Supporting strength as pre-assigned by the VCEP rule text.
BayesDel score (0.59368) was retrieved but is not used: no verified published calibration threshold for BayesDel is available to this pipeline, and the PTEN VCEP does not specify a BayesDel threshold for PP3/BP4, so it is treated as not_available/insufficiently calibrated per pipeline policy.
BP7 does not apply because the variant is a missense coding substitution, not synonymous or intronic.
No criteria match.
Met · 3
PS3ModerateMet (Moderate): Mighell 2018 saturation mutagenesis measured a phosphatase activity score of -3.483, well below the -1.11 pathogenic threshold.
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Reasoning
PTEN VCEP specification (cspec v3.2) defines PS3_Moderate as phosphatase activity <= -1.11 per the Mighell et al. 2018 (PMID 29706350) saturation mutagenesis massively parallel assay (mmc2.xlsx, Table S2). Direct lookup of NP_000305.3:p.(I32S) in Table S2 gives Cum_score = -3.483 (cumulative fitness/phosphatase activity score), well below the -1.11 moderate threshold, with High_conf = TRUE and High_conf_nature = 'Pass SE Filter', indicating this is a directly measured (not imputed) high-confidence data point, not a random-forest-imputed value. This is a validated, VCEP-endorsed functional assay with defined quantitative pathogenic threshold and passing internal quality-control (standard error) filters, satisfying PS3 at Moderate strength per the PTEN-specific rule. The VCEP rules reserve PS3_Strong for splicing assays (RNA/mini-gene) and PS3_Supporting for less-established assays; the Mighell et al. phosphatase assay is explicitly calibrated only to the Moderate tier, so Moderate is the correct and maximum strength assignable from this evidence.
Rule
PTEN VCEP cspec v3.2 PS3_Moderate: Phosphatase activity <= -1.11 per Mighell et al. 2018 (PMID 29706350), Table S2 Cum_score.
Evidence considered
PTEN cspec v3.2 PS3 rule: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product... Phosphatase activity <= -1.11 per Mighell et al. 2018, PMID: 29706350' assigns Moderate strength.
mmc2.xlsx Table S2 (Mighell et al. 2018 saturation mutagenesis dataset, PMID 29706350) direct row lookup for Variant='I32S', Change='Ile32Ser': Cum_score = -3.483131746, Cum_SE = 0.383916646, High_conf = TRUE, High_conf_nature = 'Pass SE Filter', Imputed_Score = 'NA' (i.e. directly measured, not imputed).
Cum_score of -3.483 is well below the VCEP PS3_Moderate cutoff of <= -1.11, indicating markedly reduced phosphatase activity consistent with a damaging functional effect.
Still missing
No orthogonal in vitro or in vivo functional assay (e.g., independent phosphatase activity assay, AKT phosphorylation assay, transgenic model) is available in the case bundle to allow escalation beyond Moderate strength.
ClinVar criterion-lead PMID 39358013 (Margot et al. 2024, PTEN germline non-truncating variant classification) is cited by the matching ClinVar submission and its title suggests possible functional/classification relevance, but no full text or OCR text was available in this case's publications folder to confirm whether it independently reports variant-specific functional data for I32S.
PM2SupportingMet (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the <0.001% population-absence threshold.
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Reasoning
PM2 Supporting is met under the PTEN VCEP specification. The exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, satisfying the specified population-absence requirement of <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; no subpopulation allele count requiring the <0.00002 (0.002%) condition is reported.
Rule
Supporting: absent in population; databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population, with <0.00002 (0.002%) required in a subpopulation if multiple alleles are present.
Evidence considered
gnomAD v2.1 reports the exact genomic variant 10-89653797-T-G as absent.
gnomAD v4.1 reports the exact genomic variant chr10-87894040-T-G as absent.
gnomAD-Canada v1.0 reports the exact genomic variant 10-87894040-T-G as absent.
The PTEN VCEP specification permits PM2 at Supporting strength when the variant is absent or has allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; if multiple alleles are present in a subpopulation, that subpopulation frequency must be <0.00002 (0.002%).
PP3SupportingMet (Supporting): REVEL score 0.967 exceeds the VCEP's >0.7 pathogenic-supporting threshold for missense variants.
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Reasoning
NM_000314.6:c.95T>G (p.Ile32Ser) is a missense variant. The PTEN VCEP (ClinGen CSPEC v3.2) PP3 specification states the rule is primarily for synonymous/intronic splicing variants (SpliceAI + VarSeak concordance) but explicitly extends: 'May also be applied to missense variants with REVEL score > 0.7.' The local REVEL lookup returns a score of 0.967 for this variant, which exceeds the VCEP's 0.7 pathogenic-supporting threshold. Per VCEP commentary, this REVEL threshold was itself calibrated via Bayesian OddsPath analysis (Tavtigian et al. 2018 framework) but downgraded to Supporting strength because the VCEP also applies PP2 for missense variants in PTEN, avoiding double-counting of the same underlying missense-deleteriousness signal. The splicing (SpliceAI/VarSeak) sub-path of PP3 is not applicable here because that sub-path is restricted by the VCEP to synonymous or intronic variants; this is a missense coding substitution, so the missense-REVEL sub-path governs and is applied directly as pre-assigned by the VCEP's own PP3 rule.
PTEN VCEP CSPEC v3.2 PP3 rule (defaultStrength Pathogenic Supporting): 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product... Missense variants: REVEL score > 0.7.' VCEP commentary notes REVEL>0.7/<0.5 thresholds were calibrated to moderate OddsPath strength via Tavtigian et al. 2018 Bayesian framework, then downgraded to Supporting because PP2 is also applied for PTEN missense variants.
Local REVEL predictor lookup (source_registry key 'revel') returns score 0.967 for NM_000314.6:c.95T>G, exceeding the VCEP's PP3 threshold of >0.7.
BA1Not met: variant is absent from gnomAD, with no allele frequency exceeding the >0.056% BA1 threshold.
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Reasoning
BA1 is not met. The PTEN c.95T>G (p.Ile32Ser) variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; therefore no filtering allele frequency exceeds the PTEN-specific BA1 threshold of >0.00056 (0.056%).
Rule
gnomAD Filtering allele frequency >0.00056 (0.056%)
Evidence considered
gnomAD v2.1 reports the exact genomic variant 10-89653797-T-G as absent.
gnomAD v4.1 reports the exact genomic variant chr10-87894040-T-G as absent.
gnomAD-Canada v1.0 reports the exact genomic variant 10-87894040-T-G as absent.
The PTEN VCEP specification defines BA1 as gnomAD Filtering allele frequency >0.00056 (0.056%).
BS1Not met: variant is absent from gnomAD, so no allele frequency falls in the BS1 range of 0.00043% to 0.056%.
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Reasoning
BS1 is not met. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so there is no observed allele frequency in the PTEN-specific BS1 ranges (0.0000043 to 0.00056).
Rule
Strong: gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%); Supporting: allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).
Evidence considered
gnomAD v2.1 reports the exact genomic variant 10-89653797-T-G as absent.
gnomAD v4.1 reports the exact genomic variant chr10-87894040-T-G as absent.
gnomAD-Canada v1.0 reports the exact genomic variant 10-87894040-T-G as absent.
The PTEN VCEP specification defines BS1 Strong for gnomAD Filtering allele frequency 0.000043 to 0.00056 and BS1 Supporting for 0.0000043 to 0.000043.
BS3Not met: measured phosphatase activity score -3.483 is far below zero, indicating damaging rather than benign function.
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Reasoning
The PTEN VCEP rule for BS3_Supporting requires phosphatase activity >0 per Mighell et al. 2018 (PMID 29706350). The directly measured Cum_score for I32S in Table S2 of mmc2.xlsx is -3.483131746 (High_conf = TRUE, not imputed), far below zero and consistent with a damaging, not benign, functional effect. This directly contradicts the BS3 threshold, so BS3 is not met.
Rule
PTEN VCEP cspec v3.2 BS3_Supporting: Phosphatase activity >0 per Mighell et al. 2018 (PMID 29706350).
Evidence considered
PTEN cspec v3.2 BS3 rule: 'In vitro or in vivo functional study or studies showing no damaging effect on protein function... Phosphatase activity >0 per Mighell et al. 2018, PMID: 29706350' is required for BS3_Supporting.
mmc2.xlsx Table S2 direct lookup for I32S: Cum_score = -3.483131746 (well below 0), High_conf = TRUE, High_conf_nature = 'Pass SE Filter', showing markedly reduced (damaging) phosphatase activity, the opposite of the benign threshold required by BS3.
BP4Not met: REVEL score 0.967 is far above the <0.5 benign-supporting threshold.
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Reasoning
The PTEN VCEP BP4 specification applies the mirror-image REVEL threshold to PP3: missense variants with REVEL score < 0.5 qualify for BP4_Supporting. This variant's REVEL score (0.967) is far above that threshold, and well above the intermediate REVEL 0.5-0.7 zone that would leave the criterion unassessed. BP4 is therefore not met. The splicing (SpliceAI/VarSeak) sub-path of BP4 is likewise not applicable since it is restricted to synonymous/intronic variants per the VCEP spec, and this variant is missense.
Rule
PTEN VCEP CSPEC v3.2 BP4: missense REVEL score < 0.5 -> BP4_Supporting; not met (REVEL=0.967)
Evidence considered
PTEN VCEP CSPEC v3.2 BP4 rule (defaultStrength Benign Supporting): 'Missense variants: REVEL scores < 0.5' required for BP4; the observed REVEL score of 0.967 fails this threshold, so BP4 is not met.
PS1Not assessed: insufficient evidence was available to determine whether this amino acid change matches a known pathogenic variant.
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Reasoning
PS1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: evidence_refs must contain only source_registry keys
attempt 2: evidence_refs must contain only source_registry keys
attempt 3: evidence_refs must contain only source_registry keys
PS2Not assessed: no confirmed de novo observation with proband phenotype, family history, or maternity/paternity documentation was available.
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Reasoning
The PTEN Expert Panel specification requires a de novo observation in a patient with the disease and no family history; Strong requires confirmation of both maternity and paternity, while Very Strong requires the specified combination of proven and assumed observations. The case bundle contains only a ClinVar-derived signal that the variant was observed de novo in at least one individual, without proband-level phenotype, family-history, maternity, paternity, or segregation documentation. PS2 therefore cannot be assigned.
Rule
PTEN V3.2 PS2: Strong for de novo occurrence with both maternity and paternity confirmed in a patient with disease and no family history; Very Strong for two proven, four assumed, or one proven plus two assumed de novo observations.
Evidence considered
The PTEN Expert Panel specification states that PS2 Strong requires a de novo observation with both maternity and paternity confirmed in a patient with disease and no family history; its Very Strong rule requires two proven, four assumed, or one proven plus two assumed de novo observations.
The ClinVar evidence audit reports a signal that in at least one individual the variant was observed to be de novo, but the bundle does not provide the individual-level parental testing, phenotype, or family-history details needed to apply PS2.
Still missing
Proband-level clinical phenotype and confirmation of PTEN hamartoma tumor syndrome
Documented absence of family history
Parental testing results confirming or failing to confirm maternity and paternity
Number of independent de novo observations and whether each is proven or assumed
PS4Not assessed: no case-control counts, phenotype-specificity scores, or enrichment statistics for this variant were available.
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Reasoning
The PTEN Expert Panel specifies PS4 using a phenotype-specificity score or a significant excess of the exact variant in affected individuals compared with controls. The case bundle provides no proband phenotype, specificity-score components, case series, case-control counts, or enrichment statistics for NM_000314.6:c.95T>G (p.Ile32Ser). The exact-variant ClinVar record is a single laboratory submission and cannot substitute for independent PS4 evidence.
Rule
PTEN V3.2 PS4: Very Strong for probands with specificity score >=16; Strong for score 4-15.5 or significantly increased prevalence in affected individuals versus controls; Moderate for score 2-3.5; Supporting for a phenotype specific for disease with a single genetic etiology or score 1-1.5.
Evidence considered
The PTEN Expert Panel version 3.2 framework assigns PS4 Very Strong for a specificity score of at least 16, Strong for a score of 4-15.5 or significant case-control enrichment, Moderate for a score of 2-3.5, and Supporting for a disease-specific phenotype or score of 1-1.5.
The exact ClinVar record for NM_000314.8(PTEN):c.95T>G (p.Ile32Ser) has one single-submitter laboratory classification and no expert-panel submission; this is not independent PS4 case evidence.
Mighell et al. describe substantial variability in PTEN-associated neurological and tumor phenotypes and state that the phenotype of a given PTEN mutation cannot currently be predicted, but the reviewed text does not mention p.Ile32Ser or provide exact-variant PS4 case-control data.
Still missing
Patient-level phenotype and PTEN phenotype-specificity score are not provided.
No exact-variant case series with ascertainment and affected-individual counts is available.
No control frequency, case-control comparison, or statistical enrichment estimate is available.
PM1Not assessed: insufficient evidence was available to evaluate location in a PTEN functional domain or mutational hotspot.
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Reasoning
PM1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: evidence_refs must contain only source_registry keys
attempt 2: evidence_refs must contain only source_registry keys
attempt 3: evidence_refs must contain only source_registry keys
PM5Not assessed: insufficient evidence was available to assess other pathogenic missense changes at this same residue.
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Reasoning
PM5 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: evidence_refs must contain only source_registry keys
attempt 2: evidence_refs must contain only source_registry keys
attempt 3: evidence_refs must contain only source_registry keys
PM6Not assessed: no assumed de novo observation with documented phenotype and family history was available.
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Reasoning
The PTEN Expert Panel specification permits PM6 for assumed de novo observations without confirmation of maternity and paternity, with strength dependent on the number of probands/observations and the phenotype and family-history requirements. The bundle does not provide sufficient proband-level documentation to establish an assumed de novo observation in a patient with disease and no family history, nor the number of qualifying observations. PM6 cannot be assigned.
Rule
PTEN V3.2 PM6: Moderate for an assumed de novo observation without confirmed maternity and paternity in a patient with disease and no family history; Strong and Very Strong require the specified higher observation counts or qualifying phenotype conditions.
Evidence considered
The PTEN Expert Panel specification states that PM6 Moderate requires an assumed de novo observation without confirmation of maternity and paternity in a proband with disease and no family history; Strong requires two presumed de novo probands or the specified highly specific phenotype exception; Very Strong requires the specified combination of proven and assumed observations.
ClinVar-derived evidence mentions de novo occurrence in at least one individual but does not document the qualifying clinical, family-history, parental-testing, or observation-count details required for PM6.
Still missing
A documented assumed de novo observation linked to this variant
PP1Not assessed: no family segregation or meiosis data were available for this variant.
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Reasoning
No family segregation data, affected relatives, phase information, or countable meioses for NM_000314.6:c.95T>G are provided in the case bundle. The PTEN Expert Panel specification requires 3 or 4 meioses for PP1 Supporting, 5 or 6 for PP1 Moderate, and at least 7 meioses across at least two families for PP1 Strong. PP1 cannot be assigned.
Rule
PTEN V3.2 PP1: Supporting requires co-segregation in multiple affected family members with 3 or 4 meioses; Moderate requires 5 or 6 meioses; Strong requires at least 7 meioses across at least two families.
Evidence considered
The PTEN Expert Panel specification requires 3 or 4 observed meioses for PP1 Supporting, 5 or 6 meioses for PP1 Moderate, and at least 7 meioses across at least two families for PP1 Strong.
The case-evidence bundle contains no variant-specific segregation observations or meiosis count for this family or any other family.
Still missing
Affected relatives carrying the variant
Unaffected relatives tested and their phenotypes
Pedigree/family identifiers and clinical phenotype consistency
Countable informative meioses
Evidence from at least one or more families sufficient for the requested strength
PP2Not assessed: insufficient evidence was available to evaluate the gene's rate of benign missense variation.
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Reasoning
PP2 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: evidence_refs must contain only source_registry keys
attempt 2: evidence_refs must contain only source_registry keys
attempt 3: evidence_refs must contain only source_registry keys
BS2Not assessed: no homozygous observations of the variant in healthy individuals were documented.
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Reasoning
BS2 cannot be assessed from the case-evidence bundle. No confirmed homozygous observation of the variant in a healthy or PHTS-unaffected individual, and no two unconfirmed homozygous observations with clinical context, are documented.
Rule
Strong: observed in the homozygous state in a healthy or PHTS-unaffected individual; one observation if homozygous status is confirmed, two if not confirmed. Supporting: two homozygous observations with no clinical data, or a qualifying BS2 observation when BS1 is also applied.
Evidence considered
The consolidated case-evidence bundle contains population absence results but does not document any homozygous observations or healthy/PHTS-unaffected individual data for this variant.
Still missing
Need documented homozygous observations for NM_000314.6:c.95T>G, including confirmation of homozygous status and the health or PHTS-unaffected status of the individuals.
BS4Not assessed: no non-segregation data in affected family members were available.
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Reasoning
No variant-specific non-segregation data are provided. The PTEN Expert Panel specification requires lack of segregation in affected members of one family for BS4 Supporting and two or more families for BS4 Strong, while cautioning that phenocopies and more than one pathogenic variant can confound apparent non-segregation. These data are absent, so BS4 cannot be assigned.
Rule
PTEN V3.2 BS4: Supporting for lack of segregation in affected members of one family; Strong for lack of segregation in affected members of two or more families, with consideration of phenocopies and alternate pathogenic variants.
Evidence considered
The PTEN Expert Panel specification states that BS4 Supporting requires lack of segregation in affected members of one family and BS4 Strong requires this in two or more families; it cautions that phenocopies and multiple pathogenic variants may mimic lack of segregation.
The case-evidence bundle contains no affected-relative testing results, pedigree data, or family-specific non-segregation observations for this variant.
Still missing
Affected relatives tested who do not carry the variant
Family-level phenotype and molecular-testing records
Number of families demonstrating non-segregation
Assessment of phenocopy or alternate pathogenic-variant explanations
BP1Not assessed: insufficient evidence was available to evaluate whether only truncating variants cause disease in this gene.
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Reasoning
BP1 could not be assessed because its agent did not produce valid output.
Still missing
attempt 1: evidence_refs must contain only source_registry keys
attempt 2: evidence_refs must contain only source_registry keys
attempt 3: evidence_refs must contain only source_registry keys
BP2Not assessed: no data on phase with a pathogenic PTEN variant or in-trans observations were available.
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Reasoning
BP2 is applicable under the PTEN Expert Panel Specifications at Supporting strength when the variant is observed in trans with a pathogenic or likely pathogenic PTEN variant, or when there are at least three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants. The case-evidence bundle provides no documented affected-proband observation, partner PTEN variant, phase determination, or qualifying cis/phase-unknown observations for NM_000314.6:c.95T>G (p.Ile32Ser). The criterion therefore cannot be assessed.
Rule
Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.
Evidence considered
PTEN Expert Panel Specifications Version 3.2 define BP2 as Supporting when the variant is observed in trans with a pathogenic or likely pathogenic PTEN variant, or after at least three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants.
The consolidated case-evidence bundle contains no qualifying phase, affected-proband, or allelic co-occurrence data for this variant.
Still missing
Documented co-occurrence with a pathogenic or likely pathogenic PTEN variant is needed, including confirmed trans phase, or at least three qualifying cis/phase-unknown observations with different pathogenic or likely pathogenic PTEN variants.
BP5Not assessed: no alternate pathogenic molecular diagnosis or non-overlapping family history was available.
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Reasoning
The PTEN Expert Panel allows BP5 at Supporting strength only when the variant is found in a case with an alternate highly penetrant molecular basis for disease and the patient's personal or family history demonstrates no overlap with PTEN. The bundle contains no alternate pathogenic molecular diagnosis and no patient or family history sufficient to establish non-overlap.
Rule
PTEN V3.2 BP5 Supporting: Variant found in a case with an alternate molecular basis for disease; the other gene/disorder must be highly penetrant and the patient's personal/family history must demonstrate no overlap between the other gene/disorder and PTEN.
Evidence considered
The PTEN Expert Panel version 3.2 BP5 rule requires an alternate highly penetrant molecular basis for disease and a personal/family history showing no overlap between that disorder and PTEN.
The consolidated case-evidence bundle contains no alternate molecular diagnosis or qualifying personal/family-history assessment.
Still missing
No alternate highly penetrant molecular diagnosis is documented for the patient.
No patient or family history is provided to demonstrate absence of overlap with PTEN hamartoma tumor syndrome.
Not applicable · 8· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: missense change produces no premature stop, frameshift, or canonical splice disruption, which PVS1 requires.
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Reasoning
NM_000314.6:c.95T>G / NP_000305.3:p.(Ile32Ser) is a missense substitution. The governing ClinGen PTEN VCEP specification (v3.2) directs PVS1 assessment via the PTEN-specific PVS1 decision tree, which is scoped exclusively to null-variant classes (nonsense, frameshift, canonical GT-AG splice site disruption, and single/multi-exon deletions/CNVs). The variant-level PVS1 assessment in this case explicitly classifies consequence_class as missense, canonical_splice_consensus as false, and states the variant does not fall into any generic null-variant bucket (nonsense, frameshift, or canonical splice). A missense substitution does not create a premature stop codon, frameshift, or disrupt canonical splice donor/acceptor sites, so it is not eligible for NMD-based or truncation-based PVS1/PVS1_Moderate assignment under either the PTEN VCEP decision tree or the generic ClinGen SVI PVS1 framework.
Rule
PTEN VCEP PVS1 decision tree (null variants only: nonsense/frameshift/canonical splice/CNV) does not apply to missense substitutions.
Evidence considered
pvs1_variant_assessment.consequence_class = 'missense'; canonical_splice_consensus = false; variant_bucket = 'other'; rationale states variant does not fall into default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical +/-1,2 splice consensus.
PTEN VCEP index guidance (PVS1_DecisionTree_PTEN.pdf) scopes the PTEN-specific PVS1 decision tree to null variant types only: nonsense, frameshift, canonical GT-AG splice site disruptions, and single/multi-exon CNV deletions, using the p.D375 (c.1121) NMD positional threshold; this variant's consequence class (missense) is outside that scope.
PTEN CSPEC v3.2 lists PVS1 defaultStrength Pathogenic Very Strong with rule text 'Use PTEN PVS1 decision tree' for the null-variant strengths (Very Strong/Strong/Moderate); none apply because the variant is not a null variant.
PM3VCEPNot applicable: the PTEN Expert Panel specification designates PM3 as not applicable to this gene.
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Reasoning
The ClinGen PTEN Expert Panel Specifications, Version 3.2, explicitly designate PM3 as not applicable to PTEN. Therefore, phase or affected-proband observations cannot activate PM3 for this PTEN variant.
VCEP rule
This rule is not applicable to PTEN.
Evidence considered
PTEN Expert Panel Specifications Version 3.2 state that PM3 is not applicable to PTEN.
The framework identifies PTEN hamartoma tumor syndrome as autosomal dominant, and the PTEN-specific framework does not permit PM3 use.
PM4N/ANot applicable: missense substitution alters one amino acid without changing protein length, so in-frame indel or stop-loss rules do not apply.
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Reasoning
PM4 under the PTEN VCEP specification is restricted to protein length-changing events: in-frame insertions/deletions in a non-repeat region, in-frame indels affecting a catalytic motif residue, or stop-loss variants causing protein extension. c.95T>G is a single-nucleotide substitution producing a missense change, p.(Ile32Ser); it changes a single amino acid residue without altering protein length, reading frame, or the stop codon. There is no in-frame insertion/deletion and no stop-loss/extension event, so the PM4 criterion class does not apply to this variant type.
Rule
PTEN VCEP PM4 (in-frame indel outside repeat region / stop-loss extension only) does not apply to missense substitutions.
Evidence considered
PTEN CSPEC v3.2 PM4 rule: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants...variants causing protein extension' - requires an indel or stop-loss consequence class.
pvs1_variant_assessment confirms consequence_class = 'missense' (single amino acid substitution, no length change) for NM_000314.6:c.95T>G / p.(Ile32Ser).
PP4VCEPNot applicable: the PTEN Expert Panel specification designates PP4 as not applicable to this gene.
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Reasoning
PP4 is explicitly designated Not Applicable in the ClinGen PTEN Expert Panel version 3.2 specification. No generic PP4 assessment is used because an applicable gene-specific specification exists.
VCEP rule
PTEN V3.2 PP4: Not Applicable.
Evidence considered
The PTEN Expert Panel version 3.2 criterion table marks PP4 as Not Applicable.
PP5VCEPNot applicable: the PTEN specification excludes PP5, and no expert-panel submission exists for this exact variant.
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Reasoning
PP5 is explicitly Not Applicable in the PTEN Expert Panel version 3.2 specification. Independently, the exact ClinVar record has only a single laboratory submission with review status criteria provided, single submitter and zero expert-panel submissions. Therefore the exact-variant expert-panel prerequisite for PP5 is not met; the laboratory classification and cited publications cannot trigger PP5.
VCEP rule
PTEN V3.2 PP5: Not Applicable; this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic assertions are required by the task instruction, and none is present.
Evidence considered
The PTEN Expert Panel version 3.2 specification states that PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
ClinVar Variation ID 4744225 matches NM_000314.8:c.95T>G (p.Ile32Ser) exactly, but reports one clinical-laboratory submission classified Likely pathogenic with review status criteria provided, single submitter and no expert-panel submissions.
The reviewed ClinVar-linked publications do not establish an exact-variant ClinVar expert-panel assertion.
BP3VCEPNot applicable: missense substitution involves no in-frame indel in a repetitive region.
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Reasoning
The PTEN VCEP specification (v3.2) explicitly marks BP3 as Not Applicable for this gene. Independently, BP3 as generically defined (in-frame indel in a repetitive region without a known function) is not relevant here because c.95T>G is a missense substitution with no protein length change, insertion, or deletion; there is no repeat-region in-frame indel event to evaluate.
VCEP rule
PTEN VCEP designates BP3 Not Applicable; generic BP3 (repeat-region in-frame indel) is also inapplicable to a missense substitution.
Evidence considered
PTEN CSPEC v3.2 explicitly lists BP3 applicability as 'Not Applicable' for this gene-specific framework.
pvs1_variant_assessment confirms consequence_class = 'missense' for NM_000314.6:c.95T>G, so there is no in-frame indel or repeat-region insertion/deletion event for BP3 to evaluate.
BP6VCEPNot applicable: the PTEN specification excludes BP6, and no expert-panel benign assertion exists for this variant.
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Reasoning
BP6 is explicitly designated Not Applicable in the ClinGen PTEN Expert Panel version 3.2 specification. In addition, the exact ClinVar record has no expert-panel submission and no benign or likely-benign exact-variant expert-panel assertion. Ordinary laboratory submissions and the aggregate record cannot trigger BP6.
VCEP rule
PTEN V3.2 BP6: Not Applicable. Exact-variant ClinVar expert-panel Benign/Likely benign assertions are required by the task instruction, and none is present.
Evidence considered
The PTEN Expert Panel version 3.2 criterion table marks BP6 as Not Applicable.
ClinVar Variation ID 4744225 has one exact-matching single-submitter Likely pathogenic laboratory record, zero expert-panel submissions, and no exact-variant expert-panel Benign or Likely benign assertion.
BP7N/ANot applicable: BP7 applies only to synonymous or intronic variants; this is a missense substitution.
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Reasoning
The PTEN VCEP BP7 specification applies only to synonymous or intronic variants (at or beyond +7/-21 for intronic) with in silico splicing predictors showing no impact. NM_000314.6:c.95T>G is a missense coding substitution (p.Ile32Ser), not a synonymous or intronic variant, so BP7 is not applicable to this variant regardless of the SpliceAI score.
Rule
PTEN VCEP CSPEC v3.2 BP7: synonymous/deep-intronic only -> not applicable to missense variant
Evidence considered
PTEN VCEP CSPEC v3.2 BP7 rule restricts applicability to 'A synonymous (silent) or intronic variant at or beyond +7/-21'; this variant is a missense substitution and does not meet the variant-type gate for BP7.
Every interpreted variant in PTEN, mapped onto the exon structure of NM_000314.6. Select a row to find it on the plot.
PTENNM_000314.6
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—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -22 bp
0.064
SpliceAI acceptor gainat +1 bp
0.423
SpliceAI donor lossat +284 bp
0.000
SpliceAI donor gainat +69 bp
0.038
Pangolin splice lossmagnitude shown
-0.216
Pangolin splice gain
0.405
Other predictors
REVEL
0.967
BayesDel
0.594
How the predictions were used
PP3SupportingMet (Supporting): REVEL score 0.967 exceeds the VCEP's >0.7 pathogenic-supporting threshold for missense variants.
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Reasoning
NM_000314.6:c.95T>G (p.Ile32Ser) is a missense variant. The PTEN VCEP (ClinGen CSPEC v3.2) PP3 specification states the rule is primarily for synonymous/intronic splicing variants (SpliceAI + VarSeak concordance) but explicitly extends: 'May also be applied to missense variants with REVEL score > 0.7.' The local REVEL lookup returns a score of 0.967 for this variant, which exceeds the VCEP's 0.7 pathogenic-supporting threshold. Per VCEP commentary, this REVEL threshold was itself calibrated via Bayesian OddsPath analysis (Tavtigian et al. 2018 framework) but downgraded to Supporting strength because the VCEP also applies PP2 for missense variants in PTEN, avoiding double-counting of the same underlying missense-deleteriousness signal. The splicing (SpliceAI/VarSeak) sub-path of PP3 is not applicable here because that sub-path is restricted by the VCEP to synonymous or intronic variants; this is a missense coding substitution, so the missense-REVEL sub-path governs and is applied directly as pre-assigned by the VCEP's own PP3 rule.
PTEN VCEP CSPEC v3.2 PP3 rule (defaultStrength Pathogenic Supporting): 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product... Missense variants: REVEL score > 0.7.' VCEP commentary notes REVEL>0.7/<0.5 thresholds were calibrated to moderate OddsPath strength via Tavtigian et al. 2018 Bayesian framework, then downgraded to Supporting because PP2 is also applied for PTEN missense variants.
Local REVEL predictor lookup (source_registry key 'revel') returns score 0.967 for NM_000314.6:c.95T>G, exceeding the VCEP's PP3 threshold of >0.7.
BP4Not met: REVEL score 0.967 is far above the <0.5 benign-supporting threshold.
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Reasoning
The PTEN VCEP BP4 specification applies the mirror-image REVEL threshold to PP3: missense variants with REVEL score < 0.5 qualify for BP4_Supporting. This variant's REVEL score (0.967) is far above that threshold, and well above the intermediate REVEL 0.5-0.7 zone that would leave the criterion unassessed. BP4 is therefore not met. The splicing (SpliceAI/VarSeak) sub-path of BP4 is likewise not applicable since it is restricted to synonymous/intronic variants per the VCEP spec, and this variant is missense.
Rule
PTEN VCEP CSPEC v3.2 BP4: missense REVEL score < 0.5 -> BP4_Supporting; not met (REVEL=0.967)
Evidence considered
PTEN VCEP CSPEC v3.2 BP4 rule (defaultStrength Benign Supporting): 'Missense variants: REVEL scores < 0.5' required for BP4; the observed REVEL score of 0.967 fails this threshold, so BP4 is not met.
BP7N/ANot applicable: BP7 applies only to synonymous or intronic variants; this is a missense substitution.
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Reasoning
The PTEN VCEP BP7 specification applies only to synonymous or intronic variants (at or beyond +7/-21 for intronic) with in silico splicing predictors showing no impact. NM_000314.6:c.95T>G is a missense coding substitution (p.Ile32Ser), not a synonymous or intronic variant, so BP7 is not applicable to this variant regardless of the SpliceAI score.
Rule
PTEN VCEP CSPEC v3.2 BP7: synonymous/deep-intronic only -> not applicable to missense variant
Evidence considered
PTEN VCEP CSPEC v3.2 BP7 rule restricts applicability to 'A synonymous (silent) or intronic variant at or beyond +7/-21'; this variant is a missense substitution and does not meet the variant-type gate for BP7.
SpliceAI predicts possible splice impact for this variant (max delta score = 0.42). REVEL score = 0.967. BayesDel score = 0.59368.
8 paper records listed. 1 cited in the classification.
Cited in the classification
A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships.
Mighell TL et al. · 2018 May 3
Massively parallel saturation mutagenesis and yeast-based phosphatase activity screening of essentially all possible PTEN missense variants, reported as cumulative fitness (phosphatase activity) scores in Table S2 (mmc2.xlsx). This dataset is directly incorporated into the PTEN VCEP specification as the source for PS3/BS3 functional evidence, with PS3_Moderate assigned at Cum_score <= -1.11 and BS3_Supporting assigned at Cum_score >0.
Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory). (ClinVarID = 4744225)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.42). REVEL score = 0.967. BayesDel score = 0.59368.
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; COSV64298840, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 7.1.0.
The current version is 11.0.07.
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