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PTENc.-638C>TUncertain significance
Print report
Variant interpretation report

PTEN c.-638C>T, p.?

NM_000314.8:c.-638C>T NP_000305.3:p.? Unknown · exon 1 View identifiers
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.

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.

NCBI Gene ↗ OncoKB ↗
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.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Met at Supporting: gnomAD v4.1 total AF 2.6136547780222995e-06 is below the PTEN PM2 threshold <0.00001.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: PM2 (supporting) is the only met criterion, and no PTEN Expert Panel Version 3.2 combination rule is satisfied.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

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
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen PTEN VCEP v3.2, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 3 not met · 7 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

For NM_000314.8:c.-638C>T, the governing PTEN VCEP framework was used: PVS1 is outside the decision tree's covered null-variant categories, PM4 has no protein-length-change consequence, and BP3 is explicitly Not Applicable.

All five requested codon, residue, domain, and missense-mechanism criteria are not applicable because NM_000314.8:c.-638C>T is an upstream noncoding variant with protein consequence NP_000305.3:p.?.

PS2, PM6, PP1, and BS4 are not assessed because the available evidence contains no documented proband-parent testing, de novo observations, informative meioses, affected-relative segregation, or non-segregation data.

All three requested criteria are not_applicable because NM_000314.8:c.-638C>T is a 5' untranslated-region variant, outside the defined PP3, BP4, and BP7 scopes; no computational predictor was used to assign a criterion.

The PTEN-specific population thresholds govern: BA1 and BS1 are not met, BS2 is not met because no homozygotes are reported, and PM2 is met at Supporting strength because the allele remains below the VCEP rarity threshold.

Met · 1

PM2 SupportingMet at Supporting: gnomAD v4.1 total AF 2.6136547780222995e-06 is below the PTEN PM2 threshold <0.00001. Details ▾Hide ▴
Reasoning

The PTEN VCEP Version 3.2 permits PM2 at Supporting strength when the allele frequency is <0.00001 in gnomAD or another large sequenced population, with a <0.00002 subpopulation requirement when multiple alleles are present. The variant is absent from gnomAD v2.1, has gnomAD v4.1 total AF 2.6136547780222995e-06, and has gnomAD v3.1 non-cancer total AF 6.86106346483705e-06 with filtering AF 0.0; each observed dataset supports PM2, and the reported subpopulation observations are single-allele observations rather than multiple variant alleles.

Rule
Absent in population; allele frequency <0.00001 (0.001%) in gnomAD, and <0.00002 (0.002%) in a subpopulation when multiple alleles are present
Evidence considered
  • The PTEN VCEP Version 3.2 specifies PM2 Supporting for allele frequency <0.00001, with a <0.00002 subpopulation requirement when multiple alleles are present.
  • gnomAD v2.1 reports the variant as absent.
  • gnomAD v4.1 reports total AF 2.6136547780222995e-06 from 1/382606 alleles, with 0 homozygotes.
  • gnomAD v3.1 non-cancer reports total AF 6.86106346483705e-06 from 1/145750 alleles, filtering AF 0.0, and 0 homozygotes; its highest raw subpopulation AF is 0.005376344086021506 from 1/186 alleles.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not met · 3 · evaluated, threshold not reached

BA1 Not met: gnomAD v4.1 total AF is 2.6136547780222995e-06 versus the PTEN BA1 filtering-AF threshold >0.00056. Details ▾Hide ▴
Reasoning

The PTEN VCEP Version 3.2 BA1 rule requires gnomAD filtering allele frequency >0.00056. The variant is absent from gnomAD v2.1; gnomAD v4.1 reports total AF 2.6136547780222995e-06 and the available non-cancer gnomAD v3.1 data report filtering AF 0.0, so the BA1 threshold is not reached. The gnomAD v3.1 non-cancer 1KG:CLM subpopulation has a raw AF of 0.005376344086021506 from 1/186 alleles, but this is not a filtering AF and does not establish BA1 under the VCEP rule.

Rule
gnomAD filtering allele frequency >0.00056 (0.056%)
Evidence considered
  • The PTEN VCEP Version 3.2 specifies BA1 for gnomAD filtering allele frequency >0.00056.
  • gnomAD v2.1 reports the variant as absent.
  • gnomAD v4.1 reports total AF 2.6136547780222995e-06, with 1/382606 alleles and 0 homozygotes.
  • gnomAD v3.1 non-cancer reports filtering AF 0.0; its raw 1KG:CLM subpopulation AF is 0.005376344086021506 from 1/186 alleles and is not a filtering AF.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 Not met: gnomAD v4.1 total AF is 2.6136547780222995e-06, below the PTEN BS1 Supporting lower threshold 0.0000043. Details ▾Hide ▴
Reasoning

The PTEN VCEP Version 3.2 specifies BS1 Strong for gnomAD filtering allele frequency from 0.000043 through 0.00056, and BS1 Supporting from 0.0000043 through 0.000043. The variant is absent from gnomAD v2.1, has gnomAD v4.1 total AF 2.6136547780222995e-06, and has gnomAD v3.1 non-cancer filtering AF 0.0; therefore neither BS1 range is met. The raw 1KG:CLM AF of 0.005376344086021506 is based on 1/186 alleles and is not the calibrated filtering AF.

Rule
BS1 Strong: gnomAD filtering allele frequency 0.000043–0.00056; BS1 Supporting: 0.0000043–0.000043
Evidence considered
  • The PTEN VCEP Version 3.2 specifies BS1 Strong for filtering AF 0.000043–0.00056 and BS1 Supporting for 0.0000043–0.000043.
  • gnomAD v2.1 reports the variant as absent.
  • gnomAD v4.1 reports total AF 2.6136547780222995e-06, with 1/382606 alleles and 0 homozygotes.
  • gnomAD v3.1 non-cancer reports filtering AF 0.0; the small 1KG:CLM raw subpopulation frequency is not a filtering AF.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS2 Not met: gnomAD v4.1 and gnomAD v3.1 non-cancer each report 0 homozygotes for the variant. Details ▾Hide ▴
Reasoning

The PTEN VCEP requires observation in the homozygous state in a healthy or PHTS-unaffected individual for BS2, with one confirmed observation or two unconfirmed observations. gnomAD v4.1 reports 0 homozygotes, gnomAD v3.1 non-cancer reports 0 homozygotes, and no homozygous observation is otherwise documented in the available evidence.

Rule
Observed in the homozygous state in a healthy or PHTS-unaffected individual; one confirmed observation or two if unconfirmed
Evidence considered
  • The PTEN VCEP Version 3.2 requires a homozygous observation in a healthy or PHTS-unaffected individual; two observations are required when homozygous status is unconfirmed.
  • gnomAD v4.1 reports 0 homozygotes.
  • gnomAD v3.1 non-cancer reports 0 homozygotes.
Sources
cspec ↗gnomad_v4 ↗

Not assessed · 7 · no assessment recorded

PS2 Not assessed: no proband phenotype, parental testing, or documented de novo observation is available. Details ▾Hide ▴
Reasoning

The PTEN VCEP requires a documented de novo observation in an affected patient with no family history, with both maternity and paternity confirmed for PS2 Strong. The available case evidence contains no proband phenotype, parental testing results, maternity or paternity confirmation, family history, or documented de novo observation.

Rule
De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.
Evidence considered
  • The PTEN Expert Panel specification defines PS2 Strong as a de novo observation in a patient with the disease and no family history, with both maternity and paternity confirmed.
  • No case-level proband, parental, or de novo evidence is documented for this variant.
Still missing
  • Document the proband's PTEN-related phenotype and disease status.
  • Provide variant testing results for both biological parents, including maternity and paternity confirmation.
  • Document family history and whether the variant is absent in both parents.
Sources
cspec ↗
PS4 Not assessed: no proband specificity score or case-control result is available to compare with the PTEN PS4 thresholds (score ≥1 or odds ratio >2 with required statistical support). Details ▾Hide ▴
Reasoning

The PTEN Expert Panel specification permits PS4 from either a sufficiently powered case-control study or phenotype-specificity scores. For case-control evidence, the governing text requires an odds ratio >2 for a PHTS component phenotype, p<0.05, and a 95% confidence-interval lower limit >1.5. For the phenotype-specificity route, adults contribute 1 point per proband with Cleveland Clinic score ≥30 or 0.5 points with score 25-29, and children contribute 1 point for pediatric phenotype score ≥5 or 0.5 points for score 4; strength is PS4_Very Strong at total score ≥16, PS4 at 4-15.5, PS4_Moderate at 2-3.5, and PS4_Supporting at 1-1.5. The case contains no documented proband phenotype, Cleveland Clinic score, pediatric score, case-control odds ratio, p-value, confidence interval, affected-case count, or control comparison, so no PS4 strength can be assigned. The PTEN specification also states that PS4 may not be applied if BS1 applies; BS1 is not evaluated in this group.

Rule
PTEN EP Version 3.2: case-control odds ratio >2 with p<0.05 and 95% confidence-interval lower limit >1.5, or phenotype-specificity score bands of ≥16 (very strong), 4-15.5 (strong), 2-3.5 (moderate), or 1-1.5 (supporting).
Evidence considered
  • The ClinGen PTEN Expert Panel Version 3.2 specification states that PS4 may use a sufficiently powered case-control study with odds ratio >2, p<0.05, and 95% confidence-interval lower limit >1.5 for a PHTS component phenotype.
  • The same specification defines phenotype-specificity scoring: adult Cleveland Clinic score ≥30 contributes 1 point, score 25-29 contributes 0.5 points, pediatric score ≥5 contributes 1 point, and score 4 contributes 0.5 points, with PS4 strength bands from supporting at 1-1.5 through very strong at ≥16.
  • The case evidence contains no documented phenotype-specificity score or case-control enrichment result for NM_000314.8:c.-638C>T.
Still missing
  • Documented affected probands and phenotype details
  • Cleveland Clinic scores for adults or pediatric phenotype scores for children
  • If using case-control evidence, odds ratio, p-value, 95% confidence interval, and affected/control counts
Sources
cspec ↗
PM6 Not assessed: no presumed or proven de novo observation, affected proband, or parental testing is documented. Details ▾Hide ▴
Reasoning

The PTEN VCEP permits PM6 for an assumed de novo variant in a proband with the disease and no family history, with strength determined by the number of presumed or proven observations and parental confirmation. No presumed or proven de novo observation, proband disease documentation, family history, or parental testing is available in the case evidence.

Rule
Assumed de novo, but without confirmation of paternity and maternity, in proband with the disease and no family history.
Evidence considered
  • The PTEN Expert Panel specification defines PM6 as assumed de novo occurrence without confirmed maternity and paternity in a proband with the disease and no family history, with higher strengths requiring multiple observations.
  • No case-level presumed or proven de novo evidence is documented for this variant.
Still missing
  • Document an affected proband with a PTEN-related phenotype.
  • Provide parental testing and state whether maternity and paternity are confirmed.
  • Document absence of family history and the number of independent de novo observations, if any.
Sources
cspec ↗
PP1 Not assessed: no affected relatives, segregation results, or meioses are documented against the 3-meiosis minimum. Details ▾Hide ▴
Reasoning

The PTEN VCEP requires co-segregation with disease in multiple affected family members and at least 3 meioses for PP1 Supporting, 5 or 6 for PP1 Moderate, or at least 7 across at least two families for PP1 Strong. No affected relatives, genotype-phenotype segregation results, family structure, or meioses are documented.

Rule
Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.
Evidence considered
  • 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.
  • No family segregation or meiosis data is documented for this variant.
Still missing
  • Provide a pedigree identifying affected relatives and their clinical diagnoses.
  • Provide variant testing results for affected and unaffected informative relatives.
  • Document the number of informative meioses and the families represented.
Sources
cspec ↗
BS4 Not assessed: no affected family members or family-level non-segregation evidence is documented. Details ▾Hide ▴
Reasoning

The PTEN VCEP defines BS4 Supporting as lack of segregation in one family and BS4 Strong as lack of segregation in affected members of two or more families, while cautioning that phenocopies and multiple pathogenic variants can confound interpretation. No affected family members, family-level genotype-phenotype discordance, or non-segregation evidence is documented.

Rule
Lack of segregation in affected members of one family.
Evidence considered
  • The PTEN Expert Panel specification defines BS4 Supporting for lack of segregation in one family and BS4 Strong for lack of segregation in two or more families.
  • No family-level non-segregation or affected-relative testing evidence is documented for this variant.
Still missing
  • Provide pedigrees and clinical status for affected relatives.
  • Provide variant testing results for affected relatives demonstrating non-segregation, if present.
  • Assess phenocopies and alternative pathogenic variants before interpreting apparent non-segregation.
Sources
cspec ↗
BP2 Not assessed: no affected-proband, phase, or cis/trans observation links NM_000314.8:c.-638C>T to another pathogenic or likely pathogenic PTEN variant. Details ▾Hide ▴
Reasoning

The PTEN VCEP Version 3.2 BP2 rule requires the variant to be observed in trans with a pathogenic or likely pathogenic PTEN variant, or to have at least three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants. The available case evidence contains no affected-proband observation, second PTEN variant, phase assignment, or cis/trans documentation for NM_000314.8:c.-638C>T. Therefore BP2 cannot be assessed.

Rule
Supporting: 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
  • The ClinGen PTEN Expert Panel Version 3.2 BP2 rule requires observation in trans with a pathogenic or likely pathogenic PTEN variant, or at least three cis and/or phase-unknown observations with different pathogenic or likely pathogenic PTEN variants.
  • No affected-proband, second-variant, phase, cis, or trans observation is documented in the available case evidence for NM_000314.8:c.-638C>T.
Still missing
  • Affected-proband or family-level observations involving NM_000314.8:c.-638C>T.
  • Identification and classification of any second PTEN variant in the same individual or family.
  • Experimental or pedigree evidence establishing trans, cis, or phase-unknown status.
Sources
cspec ↗
BP5 Not assessed: no two qualifying cases with a highly penetrant alternate diagnosis and non-overlapping PTEN history are documented for this variant. Details ▾Hide ▴
Reasoning

The PTEN Expert Panel Version 3.2 specification permits BP5 at supporting strength only when the variant is found in at least two cases with an alternate molecular basis for disease, the alternate gene/disorder is highly penetrant, and the personal or family history demonstrates no overlap with PTEN. No such cases, alternate molecular diagnosis, penetrance assessment, or non-overlapping history are documented for this variant. The case evidence therefore does not establish BP5.

Rule
PTEN EP Version 3.2 BP5 Supporting: at least two cases with an alternate molecular basis; the other gene/disorder must be highly penetrant, and the patient personal/family history must show no overlap with PTEN.
Evidence considered
  • The ClinGen PTEN Expert Panel Version 3.2 specification requires at least two BP5 cases and requires a highly penetrant alternate gene/disorder plus personal and family history with no overlap between that disorder and PTEN.
  • The case evidence does not document qualifying BP5 cases or the required alternate-diagnosis and clinical-history details.
Still missing
  • At least two independent cases carrying the variant
  • Documented alternate molecular diagnoses and evidence that each alternate disorder is highly penetrant
  • Personal and family histories showing no phenotype overlap with PTEN
Sources
cspec ↗
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.-638C>T is a 5′-UTR variant with p.? and is outside the PTEN VCEP PVS1 decision tree’s null-variant categories. Details ▾Hide ▴
Reasoning

Not applicable. NM_000314.8:c.-638C>T is a 5′-UTR variant with protein consequence NP_000305.3:p.? and is not a nonsense, frameshift, canonical GT-AG splice-site, exon-deletion, or duplication variant covered by the PTEN PVS1 decision tree. The governing PTEN VCEP decision tree therefore does not provide a PVS1 assignment for this variant. The exact variant was searched in PVS1_DecisionTree_PTEN.pdf.txt under c.-638C>T, c.-638C, NP_000305.3:p.?, and p.?; no entry was found.

Rule
PTEN VCEP PVS1 decision tree
Evidence considered
  • The PTEN ClinGen VCEP framework specifies that PVS1 uses the PTEN PVS1 decision tree.
  • The PTEN PVS1 decision tree covers nonsense, frameshift, canonical GT-AG splice-site disruptions, and single- or multi-exon deletions, with NMD and p.D375 (c.1121) branching; it does not define a PVS1 path for a 5′-UTR c.-638C>T variant with p.?.
  • The case normalization identifies NM_000314.8:c.-638C>T and NP_000305.3:p.?, while the variant assessment identifies no nonsense, frameshift, or canonical ±1,2 splice-consensus consequence.
Still missing
  • No exact variant entry was found in /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/PTEN/fulltext/PVS1_DecisionTree_PTEN.pdf.txt after searching c.-638C>T, c.-638C, NP_000305.3:p.?, and p.?
Sources
cspec ↗vcep_pvs1_decisiontree_pten
PS1 N/ANot applicable: NM_000314.8:c.-638C>T has protein consequence p.? and does not produce an amino-acid change required for PS1. Details ▾Hide ▴
Reasoning

The PTEN VCEP defines PS1 for the same amino-acid change as a previously established pathogenic variant or a pathogenic splice variant at the same nucleotide position. NM_000314.8:c.-638C>T is an upstream noncoding variant with protein consequence NP_000305.3:p.? and therefore does not produce an amino-acid change to evaluate under PS1.

Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change, or a different variant at the same nucleotide position as a pathogenic splicing variant with equal or greater predicted impact.
Evidence considered
  • The PTEN Expert Panel specification defines PS1 around an established pathogenic amino-acid change; this variant is upstream noncoding with no translated residue.
Sources
cspec ↗
PS3 N/ANot applicable: the variant is upstream of the PTEN coding sequence (p.=) and the governing functional assay rule covers missense substitutions only. Details ▾Hide ▴
Reasoning

The PTEN VCEP specification limits the governing Mighell et al. saturation-mutagenesis PS3 assay rule to coding missense variants: PS3_Moderate requires a Table S2 high-confidence entry with Cum_score <= -1.11, while PS3_Supporting concerns damaging protein-function assays. NM_000314.8:c.-638C>T is upstream of the coding sequence and is predicted to have protein consequence p.(=), not a missense substitution. Direct searches of the governing mmc2.xlsx full text found no c.-638C>T or p.? entry, so no applicable PTEN phosphatase assay result exists for this variant.

Rule
PTEN VCEP PS3: PS3_Moderate requires a high-confidence Mighell et al. 2018 Table S2 variant with Cum_score <= -1.11; the governing mmc2.xlsx file is missense-specific.
Evidence considered
  • ClinGen PTEN VCEP version 3.2 specifies PS3_Moderate for Mighell et al. 2018 (PMID: 29706350) Table S2 only when the variant is listed as high confidence and has Cum_score <= -1.11; PS3_Supporting is reserved for damaging functional studies below that threshold.
  • The case normalization records NM_000314.8:c.-638C>T as upstream of the coding sequence with predicted protein consequence NP_000305.3:p.(=), so the missense-specific PTEN saturation assay rule is not applicable.
  • Direct searches of /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/PTEN/fulltext/mmc2.xlsx.txt for c.-638C>T and p.? found no matching variant entry.
Still missing
  • No entry for c.-638C>T or p.? was found in the governing file mmc2.xlsx full text; its missense-only scope does not provide an applicable assay result for this upstream variant.
Sources
cspec ↗vcep_mmc2
PM1 N/ANot applicable: the variant has no protein residue (p.?), so it cannot be evaluated against PTEN catalytic motifs 90-94, 123-130, or 166-168. Details ▾Hide ▴
Reasoning

The PTEN VCEP defines PM1 for residues in critical functional regions, specifically catalytic motifs 90-94, 123-130, and 166-168 of NP_000305.3. The authoritative vcep_materials.json domain_tables entry for PTEN is empty, and NM_000314.8:c.-638C>T has no protein residue (NP_000305.3:p.?), so no residue can be located in a domain or hotspot for PM1.

Rule
Located in a mutational hotspot and/or critical and well-established functional domain; defined to include residues in catalytic motifs 90-94, 123-130, and 166-168 of NP_000305.3.
Evidence considered
  • The PTEN Expert Panel specification limits PM1 to a mutational hotspot or critical functional domain, including catalytic motifs 90-94, 123-130, and 166-168; the variant has no translated residue.
Sources
cspec ↗
PM3 VCEPNot applicable: the PTEN VCEP Version 3.2 specification explicitly marks PM3 as not applicable for PTEN. Details ▾Hide ▴
Reasoning

The governing ClinGen PTEN Expert Panel specification, Version 3.2, explicitly designates PM3 as not applicable. PTEN hamartoma tumor syndrome is specified as autosomal dominant, and the framework does not permit PM3 for this gene/condition.

VCEP rule
PM3 is not applicable under the ClinGen PTEN Expert Panel Specification Version 3.2.
Evidence considered
  • The ClinGen PTEN Expert Panel Version 3.2 specification lists PM3 with applicability "Not Applicable".
  • The same specification identifies PTEN hamartoma tumor syndrome as autosomal dominant.
Sources
cspec ↗
PM4 N/ANot applicable: the 5′-UTR c.-638C>T substitution has p.? and no evidence of an in-frame indel, stop-loss, extension, or protein-length change. Details ▾Hide ▴
Reasoning

Not applicable. The PTEN VCEP PM4 rule requires a protein length change caused by an in-frame insertion/deletion in a non-repeat region or a stop-loss/protein-extension variant; NM_000314.8:c.-638C>T is a 5′-UTR substitution with NP_000305.3:p.? and no demonstrated protein-length change. The exact variant was not found in PVS1_DecisionTree_PTEN.pdf.txt, which is the only on-record file declared for PVS1; that file does not govern PM4.

Rule
PTEN VCEP PM4 rule
Evidence considered
  • The PTEN VCEP PM4 rule applies to protein length changes from in-frame insertions/deletions in non-repeat regions or to stop-loss variants, including protein extensions.
  • The normalized consequence is NM_000314.8:c.-638C>T with NP_000305.3:p.?, so no altered protein length is established.
Sources
cspec ↗
PM5 N/ANot applicable: NM_000314.8:c.-638C>T is noncoding with protein consequence p.? and is not a missense change at an amino-acid residue. Details ▾Hide ▴
Reasoning

The PTEN VCEP defines PM5 for a missense change at an amino-acid residue where a different pathogenic or likely pathogenic missense change has been observed, with the queried variant's BLOSUM62 score no greater than the comparator. NM_000314.8:c.-638C>T is not a missense variant and has protein consequence NP_000305.3:p.?, so PM5 cannot apply.

Rule
Missense change at an amino-acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before, with BLOSUM62 score equal to or less than the known variant.
Evidence considered
  • The PTEN Expert Panel specification requires a missense change and a comparable pathogenic or likely pathogenic missense variant at the same residue; no translated residue exists for this variant.
Sources
cspec ↗
PP2 N/ANot applicable: the upstream variant has protein consequence p.? and does not meet PP2's required missense-variant criterion. Details ▾Hide ▴
Reasoning

The PTEN VCEP defines PP2 for a missense variant in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_000314.8:c.-638C>T is upstream noncoding with protein consequence NP_000305.3:p.? and is not a missense variant.

Rule
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
Evidence considered
  • The PTEN Expert Panel specification requires a missense variant for PP2; this variant has no protein consequence and is not missense.
Sources
cspec ↗
PP3 N/ANot applicable: c.-638C>T is a 5' untranslated-region variant, outside the PTEN VCEP PP3 scope for missense or splice-region/intronic variants. Details ▾Hide ▴
Reasoning

PP3 is not applicable. NM_000314.8:c.-638C>T is a 5' untranslated-region variant (the c.- coordinate is upstream of the coding start), not a missense, intronic, or splice-region variant. The governing PTEN VCEP PP3 rule covers missense variants through REVEL and splicing variants through concordant SpliceAI and VarSeak; therefore no predictor score is evaluated for this out-of-scope variant.

Rule
PTEN VCEP version 3.2 PP3: splicing variants require concordance of SpliceAI and VarSeak; missense variants require REVEL score > 0.7.
Evidence considered
  • The HGVS coordinate c.-638C>T places the variant in the 5' untranslated region, upstream of the coding start.
  • The PTEN VCEP version 3.2 PP3 rule specifies REVEL for missense variants and concordant SpliceAI/VarSeak for splicing variants; it does not apply to a 5' untranslated-region variant.
Sources
cspec ↗
PP4 VCEPNot applicable: the PTEN VCEP explicitly excludes PP4 and incorporates phenotype specificity into PS4 Use 2 instead. Details ▾Hide ▴
Reasoning

The ClinGen PTEN Expert Panel Version 3.2 specification explicitly marks PP4 as not applicable and states that phenotype specificity is incorporated into PS4 Use 2 instead. PP4 is therefore not adjudicated independently for this PTEN variant.

VCEP rule
PTEN EP Version 3.2: PP4 is not applicable; phenotype specificity is incorporated into PS4 Use 2.
Evidence considered
  • The ClinGen PTEN Expert Panel Version 3.2 specification labels PP4 as not applicable and directs phenotype-specific evidence to PS4 Use 2.
Sources
cspec ↗
PP5 VCEPNot applicable: the PTEN VCEP excludes PP5, and the exact variant has no ClinVar record or Expert Panel pathogenic classification. Details ▾Hide ▴
Reasoning

The ClinGen PTEN Expert Panel Version 3.2 specification marks PP5 as not applicable, consistent with the requirement that PP5 be restricted to an exact-variant ClinVar Expert Panel pathogenic or likely pathogenic classification. ClinVar returned no record for NM_000314.8:c.-638C>T, so no qualifying expert-panel assertion exists.

VCEP rule
PP5 requires an exact-variant ClinVar Expert Panel Pathogenic or Likely Pathogenic classification, but the PTEN VCEP marks PP5 not applicable.
Evidence considered
  • The ClinGen PTEN Expert Panel Version 3.2 specification states that PP5 is not for use for this VCEP.
  • ClinVar returned no result for the exact variant NM_000314.8:c.-638C>T; therefore there is no exact-variant ClinVar Expert Panel Pathogenic or Likely Pathogenic classification to support PP5.
Sources
cspec ↗clinvar ↗
BS3 N/ANot applicable: the upstream variant has protein consequence p.=, whereas the governing BS3 assay evidence is restricted to functional protein variants. Details ▾Hide ▴
Reasoning

The PTEN VCEP specification limits the governing Mighell et al. saturation-mutagenesis BS3 rule to functional assessment of protein-function variants: BS3_Supporting requires phosphatase activity >0 in the Table S2 assay, and BS3_Strong requires well-established evidence of no damaging effect, including appropriate splicing studies where relevant. NM_000314.8:c.-638C>T is upstream of the coding sequence and is predicted to have protein consequence p.(=), not a missense substitution. Direct searches of the governing mmc2.xlsx full text found no c.-638C>T or p.? entry, so this protein-function assay cannot be used for BS3.

Rule
PTEN VCEP BS3: BS3_Supporting requires Mighell et al. 2018 Table S2 phosphatase activity >0; the governing mmc2.xlsx file is missense-specific.
Evidence considered
  • ClinGen PTEN VCEP version 3.2 specifies BS3_Supporting for phosphatase activity >0 per Mighell et al. 2018 (PMID: 29706350), while BS3_Strong requires well-established functional evidence showing no damaging effect.
  • The case normalization records NM_000314.8:c.-638C>T as upstream of the coding sequence with predicted protein consequence NP_000305.3:p.(=), so the missense-specific PTEN protein-function assay rule is not applicable.
  • Direct searches of /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/PTEN/fulltext/mmc2.xlsx.txt for c.-638C>T and p.? found no matching variant entry.
Still missing
  • No entry for c.-638C>T or p.? was found in the governing file mmc2.xlsx full text; no applicable benign functional assay result is available from this missense-only resource.
Sources
cspec ↗vcep_mmc2
BP1 VCEPNot applicable: the PTEN specification marks BP1 not applicable, and this variant has no protein consequence rather than a benign missense change. Details ▾Hide ▴
Reasoning

The governing PTEN Expert Panel specification marks BP1 as not applicable. Independently, BP1 is a missense-oriented benign criterion and NM_000314.8:c.-638C>T is upstream noncoding with protein consequence NP_000305.3:p.?.

Evidence considered
  • The PTEN Expert Panel specification explicitly marks BP1 as not applicable; the variant is also noncoding with protein consequence p.? rather than missense.
Sources
cspec ↗
BP3 VCEPNot applicable: the PTEN VCEP explicitly excludes BP3, and c.-638C>T is a 5′-UTR substitution rather than an in-frame deletion in a repetitive protein region. Details ▾Hide ▴
Reasoning

Not applicable. The PTEN ClinGen VCEP framework explicitly marks BP3 as Not Applicable. Independently, BP3 concerns in-frame deletions in a repetitive region, whereas NM_000314.8:c.-638C>T is a 5′-UTR substitution with NP_000305.3:p.? and is not an in-frame protein deletion. The exact variant was searched in PVS1_DecisionTree_PTEN.pdf.txt under c.-638C>T, c.-638C, NP_000305.3:p.?, and p.?; no entry was found, and that PVS1 file does not govern BP3.

VCEP rule
PTEN VCEP BP3 applicability: Not Applicable
Evidence considered
  • The PTEN ClinGen VCEP framework explicitly lists BP3 applicability as Not Applicable.
  • BP3 is defined for in-frame deletions in a repetitive region; this variant is a 5′-UTR substitution with protein consequence p.? and does not meet that consequence pattern.
Still missing
  • No exact variant entry was found in /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/PTEN/fulltext/PVS1_DecisionTree_PTEN.pdf.txt after searching c.-638C>T, c.-638C, NP_000305.3:p.?, and p.?
Sources
cspec ↗vcep_pvs1_decisiontree_pten
BP4 N/ANot applicable: c.-638C>T is a 5' untranslated-region variant, outside the PTEN VCEP BP4 scope for missense or splice-region/intronic variants. Details ▾Hide ▴
Reasoning

BP4 is not applicable. NM_000314.8:c.-638C>T is a 5' untranslated-region variant (the c.- coordinate is upstream of the coding start), not a missense, intronic, or splice-region variant. The governing PTEN VCEP BP4 rule covers missense variants through REVEL and splicing variants through concordant SpliceAI and VarSeak; therefore the unavailable SpliceAI result, Pangolin values, and absent REVEL score are not evaluated for this out-of-scope variant.

Rule
PTEN VCEP version 3.2 BP4: splicing variants require concordance of SpliceAI and VarSeak; missense variants require REVEL score < 0.5.
Evidence considered
  • The HGVS coordinate c.-638C>T places the variant in the 5' untranslated region, upstream of the coding start.
  • The PTEN VCEP version 3.2 BP4 rule specifies REVEL below 0.5 for missense variants and concordant SpliceAI/VarSeak for splicing variants; it does not apply to a 5' untranslated-region variant.
  • SpliceAI returned no score and REVEL was not found, but these predictor results are not evaluated because BP4 is out of scope for this variant.
Sources
cspec ↗
BP6 VCEPNot applicable: the PTEN VCEP excludes BP6, and the exact variant has no ClinVar record or Expert Panel benign classification. Details ▾Hide ▴
Reasoning

The ClinGen PTEN Expert Panel Version 3.2 specification marks BP6 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. In addition, ClinVar returned no record for the exact variant, so there is no exact-variant ClinVar Expert Panel Benign or Likely Benign classification that could otherwise satisfy the requested BP6 gate.

VCEP rule
BP6 requires an exact-variant ClinVar Expert Panel Benign or Likely Benign classification, but the PTEN VCEP marks BP6 not applicable.
Evidence considered
  • The ClinGen PTEN Expert Panel Version 3.2 specification states that BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
  • ClinVar returned no result for the exact variant NM_000314.8:c.-638C>T; therefore there is no exact-variant ClinVar Expert Panel Benign or Likely Benign classification to support BP6.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: c.-638C>T is a 5' untranslated-region variant, not a synonymous variant within the PTEN VCEP BP7 scope. Details ▾Hide ▴
Reasoning

BP7 is not applicable. NM_000314.8:c.-638C>T is a 5' untranslated-region variant, not a synonymous variant. The governing PTEN VCEP BP7 rule applies to synonymous or qualifying intronic variants at or beyond +7/-21 with no predicted splice impact, so no splice-prediction evidence is evaluated for this out-of-scope variant.

Rule
PTEN VCEP version 3.2 BP7: synonymous or qualifying intronic variant at or beyond +7/-21 with splice algorithms predicting no impact.
Evidence considered
  • The HGVS coordinate c.-638C>T places the variant in the 5' untranslated region, upstream of the coding start and outside the synonymous-variant scope of BP7.
  • The PTEN VCEP version 3.2 BP7 rule applies to synonymous or qualifying intronic variants at or beyond +7/-21 with no predicted splice impact.
Sources
cspec ↗

Identifiers

Gene
PTEN
Transcript
NM_000314.8
Coding (HGVS c.)
NM_000314.8:c.-638C>T
Protein (HGVS p.)
NP_000305.3:p.?
GRCh38
chr10:87863832 C>T
GRCh37
chr10:89623589 C>T
Location and type
Exon 1 · unknown

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…
gnomAD v4.1 1 / 382,606 alleles AF 2.61e-06 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 2.6e-06 · 1 / 382,606 alleles · 0 hom
Admixed American1 / 21,986 4.5e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.61365e-06; MAF= 0.00026%, 1/382606 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 4.54835e-05; MAF= 0.00455%, 1/21986 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.004
Pangolin splice gain
0.017

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: c.-638C>T is a 5' untranslated-region variant, outside the PTEN VCEP PP3 scope for missense or splice-region/intronic variants. Details ▾Hide ▴
Reasoning

PP3 is not applicable. NM_000314.8:c.-638C>T is a 5' untranslated-region variant (the c.- coordinate is upstream of the coding start), not a missense, intronic, or splice-region variant. The governing PTEN VCEP PP3 rule covers missense variants through REVEL and splicing variants through concordant SpliceAI and VarSeak; therefore no predictor score is evaluated for this out-of-scope variant.

Rule
PTEN VCEP version 3.2 PP3: splicing variants require concordance of SpliceAI and VarSeak; missense variants require REVEL score > 0.7.
Evidence considered
  • The HGVS coordinate c.-638C>T places the variant in the 5' untranslated region, upstream of the coding start.
  • The PTEN VCEP version 3.2 PP3 rule specifies REVEL for missense variants and concordant SpliceAI/VarSeak for splicing variants; it does not apply to a 5' untranslated-region variant.
Sources
cspec ↗
BP4 N/ANot applicable: c.-638C>T is a 5' untranslated-region variant, outside the PTEN VCEP BP4 scope for missense or splice-region/intronic variants. Details ▾Hide ▴
Reasoning

BP4 is not applicable. NM_000314.8:c.-638C>T is a 5' untranslated-region variant (the c.- coordinate is upstream of the coding start), not a missense, intronic, or splice-region variant. The governing PTEN VCEP BP4 rule covers missense variants through REVEL and splicing variants through concordant SpliceAI and VarSeak; therefore the unavailable SpliceAI result, Pangolin values, and absent REVEL score are not evaluated for this out-of-scope variant.

Rule
PTEN VCEP version 3.2 BP4: splicing variants require concordance of SpliceAI and VarSeak; missense variants require REVEL score < 0.5.
Evidence considered
  • The HGVS coordinate c.-638C>T places the variant in the 5' untranslated region, upstream of the coding start.
  • The PTEN VCEP version 3.2 BP4 rule specifies REVEL below 0.5 for missense variants and concordant SpliceAI/VarSeak for splicing variants; it does not apply to a 5' untranslated-region variant.
  • SpliceAI returned no score and REVEL was not found, but these predictor results are not evaluated because BP4 is out of scope for this variant.
Sources
cspec ↗
BP7 N/ANot applicable: c.-638C>T is a 5' untranslated-region variant, not a synonymous variant within the PTEN VCEP BP7 scope. Details ▾Hide ▴
Reasoning

BP7 is not applicable. NM_000314.8:c.-638C>T is a 5' untranslated-region variant, not a synonymous variant. The governing PTEN VCEP BP7 rule applies to synonymous or qualifying intronic variants at or beyond +7/-21 with no predicted splice impact, so no splice-prediction evidence is evaluated for this out-of-scope variant.

Rule
PTEN VCEP version 3.2 BP7: synonymous or qualifying intronic variant at or beyond +7/-21 with splice algorithms predicting no impact.
Evidence considered
  • The HGVS coordinate c.-638C>T places the variant in the 5' untranslated region, upstream of the coding start and outside the synonymous-variant scope of BP7.
  • The PTEN VCEP version 3.2 BP7 rule applies to synonymous or qualifying intronic variants at or beyond +7/-21 with no predicted splice impact.
Sources
cspec ↗

Statement

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here.

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 1 / 382,606 recorded alleles 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 Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.61365e-06; MAF= 0.00026%, 1/382606 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 4.54835e-05; MAF= 0.00455%, 1/21986 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here.

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).