The POLE NM_006231.4:c.5174-15C>T (NP_006222.2:p.?) intronic variant has previously been reported in somatic cancers (COSMIC; COSV57675057, n = 6 times). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
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.
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About POLE
POLE encodes the catalytic subunit of DNA polymerase epsilon, the enzyme that replicates the leading strand of DNA during cell division and participates in DNA repair. It contains a proofreading domain that corrects replication errors, keeping the accumulation of mutations in check. Germline mutations in POLE cause polyposis and predispose to colorectal cancer, and are also linked to a rare syndrome of facial dysmorphism, immunodeficiency, livedo, and short stature. Somatic mutations, particularly in the proofreading domain, occur in colorectal and endometrial cancers, where they drive an ultra-mutated tumor phenotype and are associated with better responses to immune checkpoint inhibitors.
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01The reasoning
How it was classified
The recorded framework is León-Castillo et al. 2020 custom POLE framework. 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 at Supporting: gnomAD v4.1 AF 5.01004e-06 is below the <=0.0001 PM2 threshold, with zero homozygotes among 1,596,794 alleles.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
VUS: PM2 supporting is the only applied criterion and does not satisfy a pathogenic or benign combination rule under the custom POLE framework.
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
8 / 1,596,794 alleles
gnomAD v4.1: 8 / 1,596,794 alleles. Recorded AF 5.01004e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.21525e-06; MAF= 0.00042%, 1/237234 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.90478e-05; MAF= 0.00290%, 1/34426 alleles, homozygotes = 0).
ACMG/AMP criteria under León-Castillo et al. 2020 custom POLE framework, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 5 not met · 10 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
All three requested consequence criteria are not applicable because this variant is an intronic single-nucleotide substitution at c.5174-15C>T, outside the variant classes named by PVS1, PM4, and BP3.
All five requested criteria are not applicable because the queried variant is intronic and has protein consequence p.?; the available POLE framework PM1 paths and generic PS1, PM5, PP2, and BP1 definitions are missense or amino-acid based.
The governing POLE reference files were searched for c.5174-15C>T and p.?; no exact entry was found in PATH-250-323.pdf or PATH-250-323-s002.xlsx, while PATH-250-323-s001.tif had no searchable text.
PS4 is not applicable because the local POLE rule names exact missense variants only and this variant is intronic with protein consequence p.?.
PP4 and BP5 are not assessed because the required phenotype/family-history and alternate-molecular-basis evidence is not available.
PP5 and BP6 are not met because the only exact-variant ClinVar record is a single-submitter Likely benign classification with zero expert-panel submissions.
PP3 and BP4 are not applicable because the local POLE rules are restricted to exact missense variants represented in Supplementary Table S2 or S3, and BP7 is not applicable because the variant is intronic rather than synonymous.
Population evidence supports PM2 at Supporting strength because the variant is extremely rare in gnomAD v4.1 and v2.1.
BA1 and BS1 are not met because the gnomAD v4.1 filtering grpmax FAF is 7.9e-07, far below their supplied generic frequency thresholds.
BS2 is not met because no homozygotes or other qualifying healthy-adult observation in the inheritance-relevant state are documented.
No criteria match.
Met · 1
PM2SupportingACMG_2015Met at Supporting: gnomAD v4.1 AF 5.01004e-06 is below the <=0.0001 PM2 threshold, with zero homozygotes among 1,596,794 alleles.
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Reasoning
PM2 is met at Supporting strength. No governing VCEP-specific population source is present, so the generic all-comers gnomAD sources are used. gnomAD v4.1 shows AF=5.01004e-06 from 8/1,596,794 alleles with zero homozygotes, below the supplied PM2 Supporting threshold of <=0.0001. gnomAD v2.1 independently shows AF=4.21525e-06 from 1/237,234 alleles with zero homozygotes.
Rule
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Evidence considered
gnomAD v4.1 all-comers: AF=5.01004e-06 from 8/1,596,794 alleles, homozygotes=0; this is below the supplied PM2 Supporting threshold of <=0.0001.
gnomAD v2.1 all-comers: AF=4.21525e-06 from 1/237,234 alleles, homozygotes=0.
No governing VCEP-specific PM2 source or threshold is present; the generic all-comers source is therefore used.
PP5ACMG_2015Not met: ClinVar reports one non-expert single-laboratory Likely benign submission, not an exact-variant Pathogenic or Likely pathogenic expert-panel classification.
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Reasoning
The exact variant has one ClinVar submission classified Likely benign by a single clinical laboratory with criteria provided, not an expert-panel classification. It is not a reputable exact-variant Pathogenic or Likely pathogenic expert-panel classification, so PP5 is not met under the required generic rule.
Rule
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Evidence considered
ClinVar variation 1588881 exactly matches NM_006231.4(POLE):c.5174-15C>T and reports Likely benign with review status criteria provided, single submitter; the submission audit records zero expert-panel submissions.
The generic PP5 trigger is restricted here to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; the available classification is neither.
BA1ACMG_2015Not met: gnomAD v4.1 grpmax FAF 7.9e-07 is far below the >=0.05 BA1 threshold, despite a Finnish point estimate of 4.0422e-05.
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Reasoning
BA1 is not met. No governing VCEP-specific population source is present, so the generic all-comers gnomAD v4.1 data are used. The filtering grpmax FAF is 7.9e-07, far below the supplied stand-alone threshold of >=0.05. The highest population point estimate is Finnish AF=4.0422e-05 from 2/49,478 alleles, but the required filtering FAF remains far below the BA1 threshold; the variant is present in only 8/1,596,794 total alleles with zero homozygotes.
Rule
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1ACMG_2015Not met: gnomAD v4.1 grpmax FAF 7.9e-07 is below the generic >=0.01 BS1 threshold and does not exceed the disorder-expected frequency.
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Reasoning
BS1 is not met. No governing VCEP-specific population source is present, so the generic all-comers gnomAD v4.1 data are used. The filtering grpmax FAF is 7.9e-07, well below the supplied generic default threshold of >=0.01 and therefore does not demonstrate a frequency greater than expected for the disorder. The Finnish point estimate of 4.0422e-05 from 2/49,478 alleles cannot replace the filtering FAF; because the observed frequency is far below the default, a maximum-credible-frequency calculation is not needed to reject BS1.
Rule
Allele frequency is greater than expected for the disorder.
Evidence considered
gnomAD v4.1 all-comers: filtering grpmax FAF=7.9e-07; total AF=5.01004e-06 from 8/1,596,794 alleles.
The highest population point estimate is Finnish AF=4.0422e-05 from 2/49,478 alleles; the filtering FAF, not the popmax point estimate, governs this frequency assessment.
Generic calibration threshold supplied for this case: BS1 default >=0.01; the observed filtering FAF is far below it, so no maximum-credible-frequency calculation is required.
BS2ACMG_2015Not met: gnomAD v4.1 reports zero homozygotes among 1,596,794 alleles, with no documented qualifying healthy-adult observation.
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Reasoning
BS2 is not met. gnomAD v4.1 reports zero homozygotes among 1,596,794 observed alleles, and gnomAD v2.1 reports zero homozygotes among 237,234 alleles. The available case evidence contains no qualifying observation of this variant in a healthy adult in the inheritance-relevant state, so the healthy-adult requirement is not satisfied.
Rule
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
Evidence considered
gnomAD v4.1 all-comers: homozygotes=0 among 1,596,794 alleles.
gnomAD v2.1 all-comers: homozygotes=0 among 237,234 alleles.
No qualifying healthy-adult observation in the inheritance-relevant state is documented in the available case evidence.
BP6ACMG_2015Not met: the exact variant has only a non-expert single-laboratory Likely benign ClinVar submission, not a qualifying reputable-source benign report under the required rule.
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Reasoning
The exact variant has one ClinVar submission classified Likely benign by a single clinical laboratory with criteria provided, but no expert-panel submission. Under the required generic rule, an ordinary laboratory submission and non-expert assertion cannot trigger BP6.
Rule
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Evidence considered
ClinVar variation 1588881 exactly matches NM_006231.4(POLE):c.5174-15C>T and reports Likely benign with review status criteria provided, single submitter; the submission audit records zero expert-panel submissions.
The generic BP6 trigger is restricted here to an exact-variant ClinVar expert-panel Benign or Likely benign classification; the available classification is a non-expert single-submitter assertion.
PS2ACMG_2015Not assessed: no documented proband de novo result with confirmation of both maternity and paternity is available.
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Reasoning
No proband-level de novo observation, parental genotype results, confirmation of both maternity and paternity, or family-history assessment is documented in the available case evidence. Therefore, the required evidence for PS2 cannot be evaluated.
Rule
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Evidence considered
The available case evidence contains no documented trio testing, parental genotypes, maternity or paternity confirmation, or family-history assessment for NM_006231.4:c.5174-15C>T.
Still missing
Proband-level variant observation and disease phenotype documentation
Maternal genotype and confirmed maternity
Paternal genotype and confirmed paternity
Family-history assessment
PS3ACMG_2015Not assessed: No variant-specific functional assay with validated controls or a reproducible damaging result is documented.
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Reasoning
No variant-specific in vitro or in vivo functional study was identified that evaluates NM_006231.4:c.5174-15C>T and demonstrates a damaging effect on POLE. The available case evidence contains no validated assay, assay controls, reproducibility information, or direct experimental result for this variant. Computational splice prediction and a ClinVar classification are not functional studies and therefore do not establish PS3.
Rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Evidence considered
The case materials contain no variant-specific experimental assay result for NM_006231.4:c.5174-15C>T.
SpliceAI max delta 0.068 is a computational prediction, not an in vitro or in vivo functional study.
ClinVar lists the exact variant as Likely benign from one single-submitter record, but that classification is not functional assay evidence.
Still missing
A variant-specific in vitro or in vivo functional study assessing POLE function or splicing is unavailable.
No assay controls, replication data, or validated clinical-laboratory assay performance data are available.
PM3ACMG_2015Not assessed: no recessive inheritance context, pathogenic second allele, or parent/offspring testing establishes this variant in trans.
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Reasoning
PM3 cannot be assessed because the available case evidence does not establish that the relevant POLE disorder is recessive, does not identify a pathogenic variant on the other allele, and provides no parent or offspring testing demonstrating the queried variant in trans. The case identifies NM_006231.4:c.5174-15C>T as an intronic variant, but no affected-proband or family-phase observation satisfies the criterion.
Rule
For recessive disorders, detected in trans with a pathogenic variant ... This requires testing of parents (or offspring) to determine phase.
Still missing
Disease-specific inheritance mode for the POLE condition
A confirmed pathogenic variant on the other allele
Parent or offspring testing demonstrating phase in trans
Affected-proband observation with the required biallelic genotype
PM6ACMG_2015Not assessed: no affected proband with an assumed de novo variant and unconfirmed parental origin is documented.
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Reasoning
No documented observation indicates that this variant is assumed de novo in an affected patient, and no parental testing or family-history information is available to support an unconfirmed de novo interpretation.
Rule
Assumed de novo, but without confirmation of paternity and maternity.
Evidence considered
The available case evidence provides no case report, pedigree, parental testing result, or explicit assumption of de novo origin for this variant.
Still missing
Affected proband documentation
Evidence that the variant is assumed de novo
Parental origin information showing that maternity and/or paternity is unconfirmed
Family-history assessment
PP1ACMG_2015Not assessed: no affected relatives or informative meioses are documented to evaluate co-segregation.
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Reasoning
No affected family members, informative meioses, pedigree, or variant-positive affected relatives are documented. The available evidence therefore does not permit evaluation of co-segregation in a gene definitively known to cause the disease.
Rule
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Evidence considered
The available case evidence contains no pedigree, affected-relative testing, segregation table, meiosis count, or phenotype-matched familial case data for this variant.
Still missing
Pedigree and family structure
Number and clinical status of affected relatives
Variant genotypes in affected relatives
Informative meioses and segregation phase
Definitive gene-disease relationship for the relevant phenotype
PP4ACMGNot assessed: no patient phenotype or family-history evidence is available to compare with a single-etiology disease presentation.
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Reasoning
The available case evidence does not provide a patient phenotype or family history, and therefore does not establish a phenotype highly specific for a disease with a single genetic etiology. No phenotype-specific source was available to assess PP4.
Rule
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Still missing
Patient phenotype and family history sufficient for PP4 assessment are not provided.
BS3ACMG_2015Not assessed: No variant-specific functional assay with validated controls or a reproducible nondamaging result is documented.
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Reasoning
No variant-specific in vitro or in vivo functional study was identified that evaluates NM_006231.4:c.5174-15C>T and demonstrates no damaging effect on POLE protein function or splicing. The available case evidence contains no validated assay, appropriate controls, reproducibility information, or direct experimental result supporting a benign functional effect. Computational splice prediction and a ClinVar classification are not functional studies and therefore do not establish BS3.
Rule
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
Evidence considered
The case materials contain no variant-specific experimental assay result for NM_006231.4:c.5174-15C>T.
SpliceAI max delta 0.068 is a computational prediction, not an in vitro or in vivo functional study.
ClinVar lists the exact variant as Likely benign from one single-submitter record, but that classification is not functional assay evidence.
Still missing
A variant-specific in vitro or in vivo functional study assessing absence of POLE functional or splicing damage is unavailable.
No assay controls, replication data, or validated clinical-laboratory assay performance data are available.
BS4ACMG_2015Not assessed: no affected relatives with known variant status are documented to demonstrate lack of segregation.
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Reasoning
No affected family members with known variant status are documented, so lack of segregation cannot be evaluated. There is also no family-level phenotype information to assess possible phenocopies or another pathogenic variant contributing to disease.
Rule
Lack of segregation in affected members of a family.
Evidence considered
The available case evidence contains no affected relatives, family genotypes, pedigree, or non-segregation analysis for NM_006231.4:c.5174-15C>T.
Still missing
Pedigree and affected-family-member documentation
Variant testing results for affected relatives
Phenotype assessment for possible phenocopies
Assessment for an additional pathogenic variant in the family
BP2ACMG_2015Not assessed: no family or proband data establish the variant in trans with a pathogenic dominant allele or in cis with any pathogenic variant.
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Reasoning
BP2 cannot be assessed because the available case evidence contains no affected-proband or family data showing NM_006231.4:c.5174-15C>T in trans with a pathogenic variant for a fully penetrant dominant disorder, and no data showing it in cis with a pathogenic variant in any inheritance pattern. The isolated ClinVar record and population observations do not establish phase or an allelic relationship.
Rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Still missing
Phase-resolved family or proband data
A pathogenic comparison variant
Evidence of a fully penetrant dominant disorder if applying the trans pathway
BP5ACMGNot assessed: no evidence documents an alternate molecular basis for disease in the case carrying this variant.
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Reasoning
The available evidence does not document that this variant was found in a case with an alternate molecular basis for disease. COSMIC recurrence is somatic cancer context and does not establish an alternate molecular diagnosis for the case, so BP5 cannot be assessed from the available material.
Rule
Variant found in a case with an alternate molecular basis for disease.
Still missing
A case-level alternate molecular diagnosis or other qualifying alternate molecular basis is not provided.
Not applicable · 12· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: the intronic SNV is at c.-15, outside the named PVS1 null-variant classes and canonical +1/+2 splice sites, with SpliceAI maximum delta 0.068.
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Reasoning
PVS1 is not applicable: NM_006231.4:c.5174-15C>T is an intronic SNV in exon 38i, not a nonsense, frameshift, canonical +1/+2 splice-site, initiation-codon, or single/multi-exon deletion variant. The normalized protein consequence is NP_006222.2:p.?; the case assessment records canonical_splice_consensus=false and no demonstrated loss-of-function consequence. SpliceAI's maximum delta score is 0.068, reported as no significant splice impact, so this variant does not enter a generic PVS1 null-variant path.
Rule
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Evidence considered
Variant-level assessment: NM_006231.4:c.5174-15C>T is intronic in exon 38i, has consequence_class 'unknown', canonical_splice_consensus=false, and predicted protein consequence NP_006222.2:p.?.
SpliceAI reports no significant splice impact, with DS_AG 0.003, DS_AL 0.068, DS_DG 0.009, DS_DL 0.002, and maximum delta score 0.068.
PS1N/ANot applicable: the intronic variant has protein consequence p.?, so no same-amino-acid pathogenic change can be evaluated.
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Reasoning
PS1 is not applicable because NM_006231.4:c.5174-15C>T is an intronic variant with protein consequence NP_006222.2:p.?, not an amino-acid substitution. The generic rule requires the same amino-acid change as a previously established pathogenic variant and cautions that changes affecting splicing should not be assessed at the amino-acid level. Searches of PATH-250-323.pdf, PATH-250-323-s002.xlsx, and PATH-250-323-s001.tif found no entry for c.5174-15C>T or p.?.
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Evidence considered
Variant normalization gives NM_006231.4:c.5174-15C>T and NP_006222.2:p.?, identifying an intronic non-missense change.
The governing generic PS1 rule is limited to a previously established pathogenic variant with the same amino-acid change; the rule also cautions against amino-acid-level assessment when splicing may be affected.
Still missing
No exact c.5174-15C>T or p.? entry in PATH-250-323.pdf.
No exact c.5174-15C>T or p.? entry in PATH-250-323-s002.xlsx.
PATH-250-323-s001.tif has no converted searchable text, so its contents could not be searched for the variant.
PS4N/ANot applicable: the POLE PS4 rule requires an exact recurrent missense hotspot, whereas c.5174-15C>T is intronic with protein consequence p.?.
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Reasoning
The governing León-Castillo custom POLE rule limits PS4_Supporting to exact POLE missense variants recurrent in both COSMIC and TCGA, with combined endometrial-carcinoma count >=10, and belonging to the highlighted pathogenic set. NM_006231.4:c.5174-15C>T is intronic/non-coding with predicted protein consequence p.? and is therefore outside the rule's named variant type. The exact variant notation c.5174-15C>T and the p.? notation were not found in PATH-250-323.pdf or PATH-250-323-s002.xlsx.txt. PATH-250-323-s001.tif was declared for PS4 but its converted text is unavailable, so it remains a file-level review gap; this does not change that the variant is outside the governing rule's missense applicability.
VCEP rule
Apply PS4_Supporting only when the exact POLE missense variant is recurrent in both the COSMIC and TCGA endometrial carcinoma cohorts in Supplementary Table S1, has a combined EC count >=10, and belongs to the established/pathogenic set highlighted by León-Castillo et al. 2020. Under the current package this supports p.P286R, p.V411L, p.A456P, and p.S297F. Do not upgrade above Supporting because the evidence source is somatic recurrence context rather than germline case-control evidence.
Evidence considered
León-Castillo et al. 2020 custom POLE PS4 rule: "Apply PS4_Supporting only when the exact POLE missense variant is recurrent in both the COSMIC and TCGA endometrial carcinoma cohorts in Supplementary Table S1, has a combined EC count >=10, and belongs to the established/pathogenic set highlighted by León-Castillo et al. 2020. Under the current package this supports p.P286R, p.V411L, p.A456P, and p.S297F. Do not upgrade above Supporting because the evidence source is somatic recurrence context rather than germline case-control evidence."
Case normalization identifies NM_006231.4:c.5174-15C>T as an intronic variant with NP_006222.2:p.? predicted protein consequence.
PATH-250-323-s002.xlsx Supplementary Table S1 lists recurrent coding POLE variants and contains no c.5174-15C>T or p.? entry; the listed pathogenic hotspot rows are p.P286R, p.V411L, p.A456P, and p.S297F.
PATH-250-323.pdf describes the five common pathogenic POLE mutations as P286R, V411L, S297F, A456P, and S459F and addresses somatic endometrial-carcinoma mutations, not this intronic variant.
Still missing
No exact c.5174-15C>T or p.? entry was found when searching PATH-250-323.pdf.
No exact c.5174-15C>T or p.? entry was found when searching PATH-250-323-s002.xlsx.txt (Supplementary Table S1).
PATH-250-323-s001.tif is declared for PS4 but its converted full text is unavailable and could not be searched manually in this text-only review.
PM1N/ANot applicable: the POLE framework limits PM1 to exact exonuclease-domain missense substitutions, while this variant is intronic with protein consequence p.?.
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Reasoning
PM1 is not applicable under the local POLE framework because its approved PM1 paths are restricted to exact exonuclease-domain missense substitutions, whereas this variant is intronic with protein consequence p.?. The authoritative domain_tables entry is empty, and the VCEP materials do not provide a domain route that can convert this intronic variant into PM1. Searches of PATH-250-323.pdf and PATH-250-323-s002.xlsx found no exact c.5174-15C>T or p.? entry; PATH-250-323-s001.tif was unavailable for text search.
VCEP rule
Apply PM1_Strong to the five established POLE exonuclease-domain hotspot missense variants emphasized by León-Castillo et al. 2020: p.P286R, p.V411L, p.S297F, p.A456P, and p.S459F. These are the exact hotspot substitutions repeatedly treated in the paper as pathogenic for the POLE-ultramutated phenotype in endometrial carcinoma. ... Apply PM1_Moderate to the exact non-hotspot exonuclease-domain missense variants identified in the paper as recurrent and POLE-score >=4 / classified as pathogenic in the TCGA-based analysis: p.F367S, p.L424I, p.M295R, p.P436R, p.M444K, and p.D368Y. Use this only for these exact substitutions, not all substitutions at the same codon. ... Apply PM1_Supporting to exact recurrent exonuclease-domain missense variants that the paper places in the POLE-score 3 / uncertain tier rather than the pathogenic tier: p.A465V, p.L424V, p.T278M, and p.A428T. This captures hotspot/domain context without promoting them to the paper's pathogenic set.
Evidence considered
The local POLE PM1 framework specifies PM1_Strong only for p.P286R, p.V411L, p.S297F, p.A456P, and p.S459F; PM1_Moderate only for p.F367S, p.L424I, p.M295R, p.P436R, p.M444K, and p.D368Y; and PM1_Supporting only for p.A465V, p.L424V, p.T278M, and p.A428T.
The variant is NM_006231.4:c.5174-15C>T with NP_006222.2:p.? and therefore does not match any exact missense substitution in the framework.
León-Castillo et al. reports five established pathogenic POLE exonuclease-domain mutations, while Supplementary Table S1 lists recurrent missense variants; neither searched file contains c.5174-15C>T or p.?.
Still missing
No exact c.5174-15C>T or p.? entry in PATH-250-323.pdf.
No exact c.5174-15C>T or p.? entry in PATH-250-323-s002.xlsx.
PATH-250-323-s001.tif could not be converted to searchable text and was not manually interpretable here.
vcep_materials.json has an empty domain_tables object; no authoritative POLE domain-table residue list was available.
PM4N/ANot applicable: c.5174-15C>T is an intronic SNV with protein consequence p.?, not an in-frame indel or stop-loss variant causing a protein-length change.
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Reasoning
PM4 is not applicable: NM_006231.4:c.5174-15C>T is an intronic SNV with normalized protein consequence NP_006222.2:p.?, not an in-frame insertion, in-frame deletion, or stop-loss variant. There is therefore no established protein-length change to evaluate under PM4.
Rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Evidence considered
Variant-level assessment identifies NM_006231.4:c.5174-15C>T as intronic in exon 38i with normalized protein consequence NP_006222.2:p.? and no defined protein-length change.
Sources
pvs1_variant_assessment
PM5N/ANot applicable: protein consequence p.? provides no amino-acid residue for comparison with a different pathogenic missense change.
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Reasoning
PM5 is not applicable because the variant is intronic with protein consequence p.? and therefore has no identifiable amino-acid residue at which an alternate pathogenic missense change could be assessed. The generic rule requires a novel missense change at a residue where a different missense change has previously been determined pathogenic. Searches of PATH-250-323.pdf, PATH-250-323-s002.xlsx, and PATH-250-323-s001.tif found no entry for c.5174-15C>T or p.?.
Rule
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Evidence considered
Variant normalization gives NP_006222.2:p.? for the intronic variant, so no residue or missense substitution is available for PM5 comparison.
The collected PM5 candidate artifact contains zero same-residue candidates because the normalized protein consequence has no missense residue; it is not used as independent classification evidence.
Still missing
No exact c.5174-15C>T or p.? entry in PATH-250-323.pdf.
No exact c.5174-15C>T or p.? entry in PATH-250-323-s002.xlsx.
PATH-250-323-s001.tif has no converted searchable text, so its contents could not be searched for the variant.
PP2N/ANot applicable: PP2 is a missense criterion, but this variant is intronic with protein consequence p.?.
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Reasoning
PP2 is not applicable because the governing criterion is defined for a missense variant, and this variant is intronic with protein consequence p.?. No missense mechanism or missense-variation rate can be applied to this non-missense change. Searches of PATH-250-323.pdf, PATH-250-323-s002.xlsx, and PATH-250-323-s001.tif found no entry for c.5174-15C>T or p.?.
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 variant is intronic and has protein consequence NP_006222.2:p.?, not a missense substitution.
No missense-specific gene mechanism or benign missense-rate evidence is applicable to this variant type.
Still missing
No exact c.5174-15C>T or p.? entry in PATH-250-323.pdf.
No exact c.5174-15C>T or p.? entry in PATH-250-323-s002.xlsx.
PATH-250-323-s001.tif has no converted searchable text, so its contents could not be searched for the variant.
PP3N/ANot applicable: the POLE PP3 rule is limited to exact missense variants in Tables S2/S3, while c.5174-15C>T is intronic with p.? and absent from both tables.
Details ▾Hide ▴
Reasoning
The local POLE PP3 rule applies only when the exact variant is a missense variant appearing in Supplementary Table S2 or S3, with a qualifying REVEL class and benign-result count. NM_006231.4:c.5174-15C>T is intronic (exon 38i) with predicted protein consequence p.? and is not listed in PATH-250-323-s003.xlsx or PATH-250-323-s004.xlsx. Therefore the custom PP3 missense rule is outside scope; the available SpliceAI max delta of 0.068 is not evaluated under this VCEP PP3 rule.
VCEP rule
Apply PP3_Supporting when the exact missense variant appears in Supplementary Table S2 or S3, the REVEL class is 'likely disease causing' (including minor spelling variants), and the number of benign in silico results is <=1. If the variant is absent from the supplementary tables, do not use this custom PP3 rule and fall back to the project's generic in-silico workflow.
Evidence considered
PATH-250-323-s003.xlsx, Supplementary Table S2: searched for c.5174-15C>T and p.?; no matching row was present.
PATH-250-323-s004.xlsx, Supplementary Table S3: searched for c.5174-15C>T and p.?; no matching row was present.
Case normalization identifies NM_006231.4:c.5174-15C>T as an intronic variant in exon 38i with NP_006222.2:p.?; SpliceAI max delta is 0.068, but the VCEP PP3 rule is missense-table restricted.
Still missing
No entry for c.5174-15C>T or p.? was found in PATH-250-323-s003.xlsx, Supplementary Table S2.
No entry for c.5174-15C>T or p.? was found in PATH-250-323-s004.xlsx, Supplementary Table S3.
Sources
vcep_path_250_323_s003vcep_path_250_323_s004
BP1N/ANot applicable: BP1 is a missense criterion, but this variant is intronic with protein consequence p.?.
Details ▾Hide ▴
Reasoning
BP1 is not applicable because the governing criterion is defined for a missense variant, and this variant is intronic with protein consequence p.?. A missense-specific benign mechanism cannot be applied to a non-missense intronic change. Searches of PATH-250-323.pdf, PATH-250-323-s002.xlsx, and PATH-250-323-s001.tif found no entry for c.5174-15C>T or p.?.
Rule
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Evidence considered
The variant is intronic and has protein consequence NP_006222.2:p.?, not a missense substitution.
No missense-specific disease mechanism assessment can be used to apply BP1 to this variant.
Still missing
No exact c.5174-15C>T or p.? entry in PATH-250-323.pdf.
No exact c.5174-15C>T or p.? entry in PATH-250-323-s002.xlsx.
PATH-250-323-s001.tif has no converted searchable text, so its contents could not be searched for the variant.
BP3N/ANot applicable: the variant is a single intronic SNV, not the in-frame deletion or insertion required for BP3, so repeat-region context cannot trigger it.
Details ▾Hide ▴
Reasoning
BP3 is not applicable: NM_006231.4:c.5174-15C>T is a single intronic SNV, not an in-frame deletion or insertion. The criterion's repetitive-region condition therefore cannot be reached, regardless of whether a repeat-region annotation is available.
Rule
In frame-deletions/insertions in a repetitive region without a known function.
Evidence considered
Variant-level assessment identifies NM_006231.4:c.5174-15C>T as an intronic SNV in exon 38i rather than an in-frame deletion or insertion.
Sources
pvs1_variant_assessment
BP4N/ANot applicable: the POLE BP4 rule is limited to exact missense variants in Tables S2/S3, while c.5174-15C>T is intronic with p.? and absent from both tables.
Details ▾Hide ▴
Reasoning
The local POLE BP4 rule applies only when the exact variant is a missense variant appearing in Supplementary Table S2 or S3, with a qualifying benign REVEL class and at least four benign in-silico results. NM_006231.4:c.5174-15C>T is intronic (exon 38i) with predicted protein consequence p.? and is not listed in PATH-250-323-s003.xlsx or PATH-250-323-s004.xlsx. Therefore the custom BP4 missense rule is outside scope; the available SpliceAI max delta of 0.068 is not evaluated under this VCEP BP4 rule.
VCEP rule
Apply BP4_Supporting when the exact missense variant appears in Supplementary Table S2 or S3, the REVEL class is 'Likely benign' or 'Likely-benign', and the number of benign in silico results is >=4. If the variant is absent from the supplementary tables, do not use this custom BP4 rule and fall back to the project's generic in-silico workflow.
Evidence considered
PATH-250-323-s003.xlsx, Supplementary Table S2: searched for c.5174-15C>T and p.?; no matching row was present.
PATH-250-323-s004.xlsx, Supplementary Table S3: searched for c.5174-15C>T and p.?; no matching row was present.
Case normalization identifies NM_006231.4:c.5174-15C>T as an intronic variant in exon 38i with NP_006222.2:p.?; SpliceAI max delta is 0.068, but the VCEP BP4 rule is missense-table restricted.
Still missing
No entry for c.5174-15C>T or p.? was found in PATH-250-323-s003.xlsx, Supplementary Table S2.
No entry for c.5174-15C>T or p.? was found in PATH-250-323-s004.xlsx, Supplementary Table S3.
Sources
vcep_path_250_323_s003vcep_path_250_323_s004
BP7N/ANot applicable: BP7 requires a synonymous variant, but c.5174-15C>T is intronic with p.?, so its SpliceAI max delta 0.068 is outside BP7 scope.
Details ▾Hide ▴
Reasoning
Generic ACMG/AMP BP7 is limited to synonymous variants. NM_006231.4:c.5174-15C>T is intronic, not synonymous, and has predicted protein consequence p.?. Accordingly, BP7 is not applicable regardless of the available SpliceAI max delta of 0.068; no BP7 evidence is assigned.
Rule
BP7: A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Evidence considered
Case normalization identifies NM_006231.4:c.5174-15C>T as an intronic variant in exon 38i with NP_006222.2:p.?; it is not a synonymous coding variant.
SpliceAI reports a maximum delta score of 0.068, but BP7 is not applicable because the variant is not synonymous.
Identifiers
Gene
POLE
Transcript
NM_006231.4
Coding (HGVS c.)
NM_006231.4:c.5174-15C>T
Protein (HGVS p.)
NP_006222.2:p.?
GRCh38
chr12:132641866 G>A
GRCh37
chr12:133218452 G>A
Location and type
Intron 38 · unknown
ClinVar
1588881
COSMIC
COSV57675057
Gene diagram
Every interpreted variant in POLE, mapped onto the exon structure of NM_006231.4. Select a row to find it on the plot.
POLENM_006231.4
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in POLE—Select a row to find it on the plot; use the link to open its page.
AF 5e-06 · 8 / 1,596,794 alleles · 0 hom · FAF 7.9e-07
European (Finnish)2 / 49,478
4e-05
East Asian1 / 44,832
2.2e-05
Admixed American1 / 59,990
1.7e-05
European (non-Finnish)4 / 1,178,328
3.4e-06
0 alternate alleles recorded in 6 other groups: Remaining individuals, Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4.2e-06 · 1 / 237,234 alleles · 0 hom
Admixed American1 / 34,426
2.9e-05
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.01004e-06; MAF= 0.00050%, 8/1596794 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.0422e-05; MAF= 0.00404%, 2/49478 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.21525e-06; MAF= 0.00042%, 1/237234 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.90478e-05; MAF= 0.00290%, 1/34426 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -65 bp
0.068
SpliceAI acceptor gainat -15 bp
0.003
SpliceAI donor lossat -158 bp
0.002
SpliceAI donor gainat -155 bp
0.009
Pangolin splice lossmagnitude shown
-0.007
Pangolin splice gain
0.029
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: the POLE PP3 rule is limited to exact missense variants in Tables S2/S3, while c.5174-15C>T is intronic with p.? and absent from both tables.
Details ▾Hide ▴
Reasoning
The local POLE PP3 rule applies only when the exact variant is a missense variant appearing in Supplementary Table S2 or S3, with a qualifying REVEL class and benign-result count. NM_006231.4:c.5174-15C>T is intronic (exon 38i) with predicted protein consequence p.? and is not listed in PATH-250-323-s003.xlsx or PATH-250-323-s004.xlsx. Therefore the custom PP3 missense rule is outside scope; the available SpliceAI max delta of 0.068 is not evaluated under this VCEP PP3 rule.
VCEP rule
Apply PP3_Supporting when the exact missense variant appears in Supplementary Table S2 or S3, the REVEL class is 'likely disease causing' (including minor spelling variants), and the number of benign in silico results is <=1. If the variant is absent from the supplementary tables, do not use this custom PP3 rule and fall back to the project's generic in-silico workflow.
Evidence considered
PATH-250-323-s003.xlsx, Supplementary Table S2: searched for c.5174-15C>T and p.?; no matching row was present.
PATH-250-323-s004.xlsx, Supplementary Table S3: searched for c.5174-15C>T and p.?; no matching row was present.
Case normalization identifies NM_006231.4:c.5174-15C>T as an intronic variant in exon 38i with NP_006222.2:p.?; SpliceAI max delta is 0.068, but the VCEP PP3 rule is missense-table restricted.
Still missing
No entry for c.5174-15C>T or p.? was found in PATH-250-323-s003.xlsx, Supplementary Table S2.
No entry for c.5174-15C>T or p.? was found in PATH-250-323-s004.xlsx, Supplementary Table S3.
Sources
vcep_path_250_323_s003vcep_path_250_323_s004
BP4N/ANot applicable: the POLE BP4 rule is limited to exact missense variants in Tables S2/S3, while c.5174-15C>T is intronic with p.? and absent from both tables.
Details ▾Hide ▴
Reasoning
The local POLE BP4 rule applies only when the exact variant is a missense variant appearing in Supplementary Table S2 or S3, with a qualifying benign REVEL class and at least four benign in-silico results. NM_006231.4:c.5174-15C>T is intronic (exon 38i) with predicted protein consequence p.? and is not listed in PATH-250-323-s003.xlsx or PATH-250-323-s004.xlsx. Therefore the custom BP4 missense rule is outside scope; the available SpliceAI max delta of 0.068 is not evaluated under this VCEP BP4 rule.
VCEP rule
Apply BP4_Supporting when the exact missense variant appears in Supplementary Table S2 or S3, the REVEL class is 'Likely benign' or 'Likely-benign', and the number of benign in silico results is >=4. If the variant is absent from the supplementary tables, do not use this custom BP4 rule and fall back to the project's generic in-silico workflow.
Evidence considered
PATH-250-323-s003.xlsx, Supplementary Table S2: searched for c.5174-15C>T and p.?; no matching row was present.
PATH-250-323-s004.xlsx, Supplementary Table S3: searched for c.5174-15C>T and p.?; no matching row was present.
Case normalization identifies NM_006231.4:c.5174-15C>T as an intronic variant in exon 38i with NP_006222.2:p.?; SpliceAI max delta is 0.068, but the VCEP BP4 rule is missense-table restricted.
Still missing
No entry for c.5174-15C>T or p.? was found in PATH-250-323-s003.xlsx, Supplementary Table S2.
No entry for c.5174-15C>T or p.? was found in PATH-250-323-s004.xlsx, Supplementary Table S3.
Sources
vcep_path_250_323_s003vcep_path_250_323_s004
BP7N/ANot applicable: BP7 requires a synonymous variant, but c.5174-15C>T is intronic with p.?, so its SpliceAI max delta 0.068 is outside BP7 scope.
Details ▾Hide ▴
Reasoning
Generic ACMG/AMP BP7 is limited to synonymous variants. NM_006231.4:c.5174-15C>T is intronic, not synonymous, and has predicted protein consequence p.?. Accordingly, BP7 is not applicable regardless of the available SpliceAI max delta of 0.068; no BP7 evidence is assigned.
Rule
BP7: A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Evidence considered
Case normalization identifies NM_006231.4:c.5174-15C>T as an intronic variant in exon 38i with NP_006222.2:p.?; it is not a synonymous coding variant.
SpliceAI reports a maximum delta score of 0.068, but BP7 is not applicable because the variant is not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
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= 5.01004e-06; MAF= 0.00050%, 8/1596794 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.0422e-05; MAF= 0.00404%, 2/49478 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.21525e-06; MAF= 0.00042%, 1/237234 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.90478e-05; MAF= 0.00290%, 1/34426 alleles, homozygotes = 0).
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1588881)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV57675057, n = 6 times).