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POLEc.2113C>TUncertain significance
Print report
Variant interpretation report

POLE c.2113C>T, p.(Arg705Trp)

NM_006231.4:c.2113C>T NP_006222.2:p.(Arg705Trp) Missense · exon 19 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 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.

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 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.

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

Met at supporting: gnomAD v4.1 total AF is 5.581014628459454e-06, below the generic PM2 threshold of 0.0001.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: only PM2 (supporting) is met, which does not satisfy any pathogenic, benign, or Likely Benign ACMG/AMP combination rule.

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
9 / 1,612,610 alleles

gnomAD v4.1: 9 / 1,612,610 alleles. Recorded AF 5.58101e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.42046e-05; MAF= 0.00142%, 4/281598 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.04083e-05; MAF= 0.00504%, 1/19838 alleles, homozygotes = 0); grpmax FAF= 2.242e-05.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.321 recorded score

Recorded REVEL score: 0.321. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
5 reported laboratory submissions

5 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high m

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV57693351, n = 4 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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 · 13 not met · 10 not assessed · 4 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

All five requested codon, residue, domain, and missense-mechanism criteria were assessed using the governing POLE materials first.

R705W is listed in PATH-250-323.pdf Table 1 and PATH-250-323-s002.xlsx, but it is not one of the governing PM1 exact hotspot/domain variants and no qualifying same-amino-acid or same-residue comparator was found.

The PATH-250-323-s001.tif file was unavailable for text conversion and remains an explicit evidence gap.

No PS2, PM6, PP1, or BS4 evidence can be assigned because the available records contain no proband phenotype, parental testing, pedigree, meiosis, segregation, or non-segregation data for the exact variant.

The local POLE framework does not specify these four criteria, so generic ACMG/AMP definitions were used without inferring evidence from any other criterion's classification.

PS4 is not met because the governing POLE rule requires exact recurrence in both COSMIC and TCGA, a combined count >=10, and membership in the established/pathogenic set; R705W has 0 COSMIC and 1 TCGA case and is not in that set.

PP4 and BP5 cannot be assessed without patient-level phenotype or an alternative pathogenic molecular explanation.

PP5 and BP6 are not met because the exact variant has no ClinVar expert-panel classification; all available laboratory submissions are Uncertain significance.

Met · 1

PM2 SupportingMet at supporting: gnomAD v4.1 total AF is 5.581014628459454e-06, below the generic PM2 threshold of 0.0001. Details ▾Hide ▴
Reasoning

No applicable POLE-specific population-frequency rule was retrieved; the local POLE framework customizes PM1, PS4, PP3, and BP4 only, so the supplied generic PM2 Supporting threshold of <=0.0001 applies. The variant is rare in both default all-comers datasets: gnomAD v2.1 total AF 1.4204646339817755e-05 and gnomAD v4.1 total AF 5.581014628459454e-06; their highest observed subpopulation frequencies, 5.0408307289041234e-05 and 2.230549607423269e-05 respectively, also remain below 0.0001. No governing specification requires a non-cancer or exome-only subset for PM2.

Rule
Generic PM2 Supporting: allele frequency <=0.0001; met at Supporting.
Evidence considered
  • The retrieved POLE framework does not specify BA1, BS1, BS2, or PM2 population rules, so the supplied generic ACMG/ClinGen-SVI PM2 threshold was used.
  • gnomAD v2.1 reports total AF 1.4204646339817755e-05 from 4/281598 alleles, with 0 homozygotes; the highest observed subpopulation AF is 5.0408307289041234e-05.
  • gnomAD v4.1 reports total AF 5.581014628459454e-06 from 9/1612610 alleles, with 0 homozygotes; the highest observed subpopulation AF is 2.230549607423269e-05.
  • The supplied generic PM2 Supporting threshold is <=0.0001, and both total and highest-subpopulation frequencies in both datasets are below it.
Sources
gnomad_v2 ↗gnomad_v4 ↗generic_acmg_combination_rulesPMID:25741868 ↗

Not met · 13 · evaluated, threshold not reached

PS1 Not met: governing tables identify R705W but no different pathogenic Arg705 substitution establishing the same-amino-acid-change criterion. Details ▾Hide ▴
Reasoning

PS1 is not met. The governing PATH-250-323.pdf Table 1 and PATH-250-323-s002.xlsx Supplementary Table S1 were searched for c.2113C>T, p.Arg705Trp, and p.R705W. They identify the queried R705W substitution, but no different pathogenic or likely pathogenic substitution producing the same amino-acid change at Arg705 was identified. The unavailable PATH-250-323-s001.tif is a review gap, not evidence that the variant is absent from that figure.

Rule
Generic PS1 requires a different pathogenic missense change producing the same amino-acid change; no such comparator was identified in the governing searchable materials.
Evidence considered
  • PATH-250-323.pdf Table 1 contains the queried R705W/c.2113C>T entry but no alternate Arg705 substitution was identified in the table.
  • PATH-250-323-s002.xlsx contains p.R705W/c.2113C>T and no different substitution at residue 705 in the searchable table.
Still missing
  • PATH-250-323-s001.tif could not be converted to searchable text and was not manually reviewed.
  • The exact notation p.Arg705Trp was not found in PATH-250-323.pdf or PATH-250-323-s002.xlsx; the variant is listed there as p.R705W/c.2113C>T.
Sources
vcep_path_250_323vcep_path_250_323_s002
PS4 Not met: p.R705W appears in 0 COSMIC and 1 TCGA endometrial-carcinoma case, totaling 1 versus the >=10 PS4 requirement. Details ▾Hide ▴
Reasoning

The POLE-specific PS4 rule requires the exact missense variant to be recurrent in both COSMIC and TCGA endometrial carcinoma cohorts, have a combined count >=10, and belong to the established/pathogenic set. PATH-250-323-s002 lists p.R705W/c.2113C>T with COSMIC 0, TCGA 1, and total 1; PATH-250-323 Table 1 likewise records R705W as one TCGA case, novel in EC, with POLE-score 5 but outside the established hotspot set. Therefore the exact-variant recurrence and >=10 requirements are not met. The main paper notes that the single R705W case scored 5 but states that its clinical significance is unclear, so this contextual observation does not override the governing PS4 rule.

Rule
Apply PS4_Supporting only for an exact POLE missense variant recurrent in both COSMIC and TCGA endometrial carcinoma cohorts, with combined EC count >=10, and included in the established/pathogenic set.
Evidence considered
  • PATH-250-323-s002 Supplementary Table S1 lists p.R705W/c.2113C>T with 0 COSMIC cases, 1 TCGA case, and total 1.
  • PATH-250-323 Table 1 lists R705W as one case, novel in EC, with POLE-score 5 and no established hotspot designation.
  • The paper states that the single non-exonuclease-domain R705W case scored 5, but also states that the clinical significance is unclear; this does not satisfy the POLE-specific PS4 recurrence rule.
Still missing
  • PATH-250-323-s001.tif was unavailable for text conversion and could not be independently reviewed visually.
Sources
vcep_path_250_323_s002vcep_path_250_323
PM1 Not met: R705W is exon 19 with EDM Signature 10 contribution N and is absent from the governing POLE PM1 exact-variant lists. Details ▾Hide ▴
Reasoning

PM1 is not met. No domain_tables entry is present in vcep_materials.json, so the governing local POLE rules and their complete approved exact-variant lists were reviewed. Those rules limit PM1 to the five established hotspots p.P286R, p.V411L, p.S297F, p.A456P, and p.S459F; six exact recurrent pathogenic non-hotspot exonuclease-domain variants; and four exact recurrent uncertain-tier exonuclease-domain variants. R705W is none of those listed substitutions. PATH-250-323.pdf Table 1 places R705W in exon 19, marks it as not an exonuclease-domain mutation (EDM Signature 10 contribution N), and records POLE-score 5; this does not satisfy the approved PM1 hotspot/domain rule.

Rule
Apply the local POLE PM1 specification only to its enumerated exact hotspot/domain variants; do not extend it to all substitutions or all residues in POLE.
Evidence considered
  • The governing POLE PM1 rules enumerate exact hotspot and exonuclease-domain variants; R705W is not among them.
  • PATH-250-323.pdf Table 1 records R705W in exon 19 with EDM Signature 10 contribution N and POLE-score 5.
  • PATH-250-323-s002.xlsx lists p.R705W/c.2113C>T with COSMIC count 0 and TCGA count 1, not as an approved PM1 hotspot.
Still missing
  • PATH-250-323-s001.tif could not be converted to searchable text and was not manually reviewed.
  • The exact notation p.Arg705Trp was not found in PATH-250-323.pdf or PATH-250-323-s002.xlsx; the variant is listed there as p.R705W/c.2113C>T.
Sources
vcep_path_250_323vcep_path_250_323_s002
PM5 Not met: no different pathogenic or likely pathogenic missense variant at Arg705 was identified in the governing tables. Details ▾Hide ▴
Reasoning

PM5 is not met. The governing PATH-250-323.pdf and PATH-250-323-s002.xlsx materials were searched for the queried variant and residue notation. No different pathogenic or likely pathogenic missense variant at Arg705 was identified. The case PM5 candidate summary reports zero same-residue candidates, but it is not used as the sole basis for this conclusion; the conclusion rests on the governing VCEP tables and their exact variant entries.

Rule
Generic PM5 requires an established pathogenic missense change at the same residue; no qualifying alternate Arg705 variant was found.
Evidence considered
  • PATH-250-323.pdf Table 1 includes R705W but no alternate Arg705 missense comparator classified as pathogenic or likely pathogenic.
  • PATH-250-323-s002.xlsx includes p.R705W/c.2113C>T but no alternate p.R705 substitution at residue 705.
Still missing
  • PATH-250-323-s001.tif could not be converted to searchable text and was not manually reviewed.
  • No independent same-residue comparator was available in the reviewed governing materials.
  • The exact notation p.Arg705Trp was not found in PATH-250-323.pdf or PATH-250-323-s002.xlsx; the variant is listed there as p.R705W/c.2113C>T.
Sources
vcep_path_250_323vcep_path_250_323_s002
PP2 Not met: no applicable POLE PP2 rule or validated low-benign-missense/high-pathogenic-missense dataset supports this exon 19 variant. Details ▾Hide ▴
Reasoning

PP2 is not met. The governing POLE material provides a somatic exonuclease-domain interpretation framework with exact variant rules, but it does not specify PP2 and does not establish that POLE has a high proportion of pathogenic missense variation together with a low benign missense rate for generic PP2 use. The queried R705W is outside the paper's exonuclease-domain EDM context, so the available domain and hotspot evidence cannot be generalized into PP2.

Rule
Generic PP2 requires a gene-level missense mechanism with few benign missense variants; insufficient POLE-specific evidence is available for this criterion.
Evidence considered
  • The local POLE framework specifies PM1, PS4, PP3, and BP4, but not PP2.
  • PATH-250-323.pdf distinguishes exonuclease-domain and non-exonuclease-domain mutations and does not provide a generic PP2 missense-mechanism rule for POLE.
Still missing
  • No POLE-specific PP2 specification or validated gene-level benign-missense dataset was present in the governing materials.
Sources
vcep_path_250_323
PP3 Not met: REVEL 0.321 is below the generic PP3 supporting threshold of 0.644 and the POLE table labels p.R705W Likely benign, not likely disease causing. Details ▾Hide ▴
Reasoning

The variant is missense (NM_006231.4:c.2113C>T, p.Arg705Trp/p.R705W), so the applicable computational path is REVEL only. The governing POLE supplementary Table S2 contains the exact p.R705W entry and pre-assigns REVEL class 'Likely benign' with 1 benign in-silico result; therefore the POLE custom PP3 rule (REVEL class likely disease causing and no more than 1 benign result) is not satisfied. The independent REVEL score is 0.321, below the supplied generic PP3 supporting threshold of 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). The SpliceAI max delta of 0.027 was not used because splice predictions cannot support PP3 for a missense variant. The exact variant was found in PATH-250-323.pdf and PATH-250-323-s002.xlsx, but those entries are contextual somatic/recurrent-variant material rather than a PP3-triggering computational assignment. No exact variant entry was found in PATH-250-323-s004.xlsx.

Rule
Missense variant: use REVEL only. POLE custom PP3 supporting requires exact presence in Supplementary Table S2 or S3, REVEL class likely disease causing, and no more than 1 benign in-silico result; otherwise generic PP3 supporting requires REVEL >= 0.644.
Evidence considered
  • PATH-250-323-s003.xlsx, Supplementary Table S2, exact p.R705W/c.2113C>T row: REVEL class 'Likely benign' and 1 benign result; this does not meet the POLE custom PP3 rule requiring likely disease causing and no more than 1 benign result.
  • Local REVEL score is 0.321, below the supplied generic PP3 supporting cutoff of 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
  • PATH-250-323.pdf contains the exact c.2113C>T entry, and PATH-250-323-s002.xlsx contains the exact p.R705W/c.2113C>T entry; these were reviewed as contextual/recurrent-variant material, not as a PP3-triggering computational assignment.
  • PATH-250-323-s004.xlsx was searched for c.2113C>T, p.Arg705Trp, and p.R705W; no exact entry was found.
  • SpliceAI max delta 0.027 was not used for this missense variant because PP3/BP4 evidence must come from the consequence-matched REVEL path.
Still missing
  • No exact c.2113C>T, p.Arg705Trp, or p.R705W entry was found in PATH-250-323-s004.xlsx; this is a table-specific negative search result, not evidence that computational evidence is absent.
Sources
vcep_path_250_323_s003revel
PP5 Not met: ClinVar has zero expert-panel submissions for this exact variant, and the aggregate classification is Uncertain significance. Details ▾Hide ▴
Reasoning

The exact variant is present in ClinVar as Uncertain significance, with five clinical-laboratory submissions and zero expert-panel submissions. No exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic is present. Ordinary laboratory submissions and aggregate database labels cannot trigger PP5 under the specified rule.

Rule
Apply PP5 only for an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
Evidence considered
  • The exact ClinVar record for NM_006231.4:c.2113C>T (p.Arg705Trp) has aggregate classification Uncertain significance.
  • The ClinVar submission audit reports five submissions and zero expert-panel submissions; all identified submissions are non-expert clinical-laboratory assertions.
Sources
clinvar ↗
BA1 Not met: the highest observed population AF is 5.04083e-05, far below the generic BA1 threshold of 0.05. Details ▾Hide ▴
Reasoning

No applicable POLE-specific population-frequency rule was retrieved; the local POLE framework customizes PM1, PS4, PP3, and BP4 only, so the generic ACMG/AMP BA1 threshold of >=0.05 applies. The highest observed all-comers frequency is gnomAD v2.1 East Asian AF 5.04083e-05, and gnomAD v4.1 East Asian AF 2.23055e-05, both far below 0.05. The available case evidence does not provide a governing requirement to substitute a non-cancer subset.

Rule
Generic BA1 stand-alone: allele frequency >=0.05; not met.
Evidence considered
  • The retrieved POLE framework does not specify BA1, BS1, BS2, or PM2 population rules, so generic ACMG/AMP population thresholds were used.
  • gnomAD v2.1 reports total AF 1.4204646339817755e-05 and highest observed subpopulation AF 5.0408307289041234e-05 in East Asian individuals, with 0 homozygotes.
  • gnomAD v4.1 reports total AF 5.581014628459454e-06 and highest observed subpopulation AF 2.230549607423269e-05 in East Asian individuals, with 0 homozygotes.
  • The generic BA1 stand-alone threshold is >=0.05 under the supplied ACMG/ClinGen-SVI calibration data.
Sources
gnomad_v2 ↗gnomad_v4 ↗generic_acmg_combination_rulesPMID:25741868 ↗
BS1 Not met: the highest observed population AF is 5.04083e-05, below the generic BS1 threshold of 0.01. Details ▾Hide ▴
Reasoning

No applicable POLE-specific population-frequency rule was retrieved; the local POLE framework customizes PM1, PS4, PP3, and BP4 only, so the supplied generic BS1 threshold of >=0.01 applies. The highest observed all-comers frequency is gnomAD v2.1 East Asian AF 5.04083e-05, and gnomAD v4.1 East Asian AF 2.23055e-05, both below 0.01. The available case evidence does not provide a governing requirement to substitute a non-cancer subset.

Rule
Generic BS1 strong: allele frequency >=0.01; not met.
Evidence considered
  • The retrieved POLE framework does not specify BA1, BS1, BS2, or PM2 population rules, so generic ACMG/AMP population thresholds were used.
  • gnomAD v2.1 reports total AF 1.4204646339817755e-05 and highest observed subpopulation AF 5.0408307289041234e-05 in East Asian individuals.
  • gnomAD v4.1 reports total AF 5.581014628459454e-06 and highest observed subpopulation AF 2.230549607423269e-05 in East Asian individuals.
  • The supplied generic BS1 threshold is >=0.01.
Sources
gnomad_v2 ↗gnomad_v4 ↗generic_acmg_combination_rulesPMID:25741868 ↗
BS2 Not met: gnomAD v2.1 and v4.1 each report 0 homozygotes, with no healthy-adult or penetrance evidence supporting BS2. Details ▾Hide ▴
Reasoning

The available population data show no homozygotes in either gnomAD v2.1 or gnomAD v4.1, and no variant-specific observation in healthy adults or penetrance evidence is provided to satisfy BS2. Therefore BS2 is not met; the absence of homozygotes also does not constitute positive benign evidence.

Rule
BS2 requires the variant to be observed in healthy adults in a context expected to exclude the relevant disease; no such observation is present.
Evidence considered
  • gnomAD v2.1 reports 0 homozygotes among 281598 alleles.
  • gnomAD v4.1 reports 0 homozygotes among 1612610 alleles.
  • No variant-specific healthy-adult observation or penetrance estimate is available in the reviewed evidence.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP1 Not met: POLE has established pathogenic missense exonuclease-domain variants, so a primarily truncating disease mechanism is not established for BP1. Details ▾Hide ▴
Reasoning

BP1 is not met. BP1 requires a missense variant in a gene for which disease is primarily caused by truncating variants. The governing POLE material instead documents established pathogenic missense hotspot and exonuclease-domain variants and uses missense/domain-specific interpretation for POLE; it does not establish that POLE disease is primarily truncating or provide a POLE-specific BP1 rule. Therefore BP1 cannot be applied to R705W.

Rule
Generic BP1 requires a missense variant in a gene where disease is primarily caused by truncating variants; that gene-level premise is not established for POLE.
Evidence considered
  • PATH-250-323.pdf discusses multiple established pathogenic POLE missense hotspots and recurrent exonuclease-domain missense variants.
  • The local POLE framework does not specify BP1.
Still missing
  • No POLE-specific BP1 specification or quantitative comparison of truncating versus missense disease-causing variants was present in the governing materials.
Sources
vcep_path_250_323
BP4 Not met: REVEL 0.321 exceeds the generic BP4 supporting threshold of 0.29, while the POLE table reports only 1 benign result versus the required 4. Details ▾Hide ▴
Reasoning

The variant is missense, so the applicable computational path is REVEL only. The governing POLE supplementary Table S2 contains the exact p.R705W entry and pre-assigns REVEL class 'Likely benign' with 1 benign in-silico result; the POLE custom BP4 rule requires REVEL class Likely benign plus at least 4 benign results, so it is not satisfied. The independent REVEL score is 0.321, above the supplied generic BP4 supporting threshold of 0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997), so generic BP4 is also not met. The SpliceAI max delta of 0.027 was not used because splice predictions cannot provide BP4 for a missense variant. No exact variant entry was found in PATH-250-323-s004.xlsx.

Rule
Missense variant: use REVEL only. POLE custom BP4 supporting requires exact presence in Supplementary Table S2 or S3, REVEL class Likely benign, and at least 4 benign in-silico results; otherwise generic BP4 supporting requires REVEL <= 0.29.
Evidence considered
  • PATH-250-323-s003.xlsx, Supplementary Table S2, exact p.R705W/c.2113C>T row: REVEL class 'Likely benign' but only 1 benign result; this does not meet the POLE custom BP4 rule requiring at least 4 benign results.
  • Local REVEL score is 0.321, above the supplied generic BP4 supporting cutoff of 0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
  • PATH-250-323-s004.xlsx was searched for c.2113C>T, p.Arg705Trp, and p.R705W; no exact entry was found.
  • SpliceAI max delta 0.027 was not used for this missense variant because BP4 evidence must come from the consequence-matched REVEL path.
Still missing
  • No exact c.2113C>T, p.Arg705Trp, or p.R705W entry was found in PATH-250-323-s004.xlsx; this is a table-specific negative search result, not evidence that computational evidence is absent.
Sources
vcep_path_250_323_s003revel
BP6 Not met: no exact-variant ClinVar expert-panel benign classification exists; available submissions are all Uncertain significance. Details ▾Hide ▴
Reasoning

The exact variant has no ClinVar expert-panel classification of Benign or Likely benign. The available ClinVar submissions are ordinary laboratory submissions, all classified as Uncertain significance, and the aggregate record is also Uncertain significance. These assertions cannot trigger BP6 under the specified exact-variant expert-panel rule.

Rule
Apply BP6 only for an exact-variant ClinVar expert-panel classification of Benign or Likely benign; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
Evidence considered
  • The exact ClinVar record reports aggregate classification Uncertain significance.
  • The ClinVar submission audit reports zero expert-panel submissions and no Benign or Likely benign expert-panel assertion; identified laboratory submissions are Uncertain significance.
Sources
clinvar ↗

Not assessed · 10 · no assessment recorded

PS2 Not assessed: no proband-parent testing or confirmed de novo observation is documented for NM_006231.4:c.2113C>T. Details ▾Hide ▴
Reasoning

PS2 cannot be assessed because the available case evidence contains no documented proband-parent comparison, parental testing result, maternity/paternity confirmation, or statement that NM_006231.4:c.2113C>T (NP_006222.2:p.Arg705Trp) arose de novo. The variant's ClinVar record reports germline submissions but provides no family-level de novo evidence. The local POLE framework does not specify PS2, so generic ACMG/AMP criteria apply.

Rule
Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with confirmed maternity and paternity; no qualifying evidence is documented.
Evidence considered
  • ClinVar variation 540760 contains germline submissions for NM_006231.4:c.2113C>T (p.Arg705Trp), but no documented parental testing, de novo assertion, or family segregation data.
  • The available POLE local framework specifies PM1, PS4, PP3, and BP4 only; it provides no gene-specific rule for PS2, PM6, PP1, or BS4, so generic ACMG/AMP assessment is required.
Still missing
  • Documented proband genotype and phenotype
  • Validated maternal and paternal relationships
  • Parental testing results for the exact variant
  • Assessment of parental mosaicism if the variant is absent in blood
Sources
clinvar ↗PMID:25394175 ↗PMID:25741868 ↗
PS3 Not assessed: no variant-specific validated functional assay, controls, or damaging functional readout were documented for p.Arg705Trp. Details ▾Hide ▴
Reasoning

No variant-specific validated functional assay is documented for NM_006231.4:c.2113C>T (NP_006222.2:p.Arg705Trp). The available POLE framework does not specify PS3, and the reviewed evidence contains no assay result, appropriate positive and negative controls, or biologically relevant functional readout establishing a damaging effect. OncoKB likewise reports no variant-specific reviewed functional evidence. PS3 therefore cannot be assigned.

Evidence considered
  • OncoKB reports no variant-specific reviewed functional evidence for POLE p.Arg705Trp.
  • The reviewed ACMG/AMP guidance provides general functional-evidence principles but reports no POLE-specific assay or result for this variant.
  • The local POLE framework customizes PM1, PS4, PP3, and BP4 only; it provides no PS3 specification.
Still missing
  • A biologically relevant, validated functional assay for p.Arg705Trp with appropriate positive and negative controls is needed.
  • Quantitative assay results and laboratory validation details are unavailable.
Sources
oncokb ↗PMID:25741868 ↗
PM3 Not assessed: no affected-proband, second-pathogenic-variant, or validated in-trans phase observation is available for PM3. Details ▾Hide ▴
Reasoning

PM3 cannot be assessed because the available evidence contains no affected proband observations establishing this variant in a recessive disorder, no second pathogenic or likely pathogenic variant, and no validated phase showing the variants are in trans. Family segregation, parental testing, and inheritance-mode evidence are not reported. The available POLE-specific framework does not specify PM3, and the reviewed literature extracts contain no variant-specific allelic or segregation observations.

Evidence considered
  • No case-level family, phase, affected-proband, or compound-heterozygous evidence for NM_006231.4:c.2113C>T (NP_006222.2:p.(Arg705Trp)) is present in the supplied case materials.
  • The local POLE framework specifies PM1, PS4, PP3, and BP4 only; it provides no POLE-specific PM3 rule.
  • The extracted reviewed publications contain no variant-specific allelic or segregation observations for this variant.
Still missing
  • Affected-proband observations attributable to this variant
  • A second pathogenic or likely pathogenic allele in the same proband
  • Validated cis/trans phase or parental testing
  • Reliable inheritance-mode evidence relevant to applying PM3
PM6 Not assessed: no unconfirmed de novo observation or parental genotyping is documented for this POLE variant. Details ▾Hide ▴
Reasoning

PM6 cannot be assessed because no unconfirmed de novo observation is reported for NM_006231.4:c.2113C>T (NP_006222.2:p.Arg705Trp), and no proband or parental clinical/genotyping details are available. ClinVar lists the variant as uncertain significance without a family-level de novo observation. The local POLE framework does not specify PM6, so generic ACMG/AMP criteria apply.

Rule
Generic ACMG/AMP PM6: assumed de novo occurrence without confirmation of maternity and paternity; no qualifying evidence is documented.
Evidence considered
  • ClinVar variation 540760 reports the exact variant as uncertain significance, but the available submissions do not document an unconfirmed de novo occurrence or parental genotypes.
  • No reviewed paper extraction reports the exact POLE variant in a de novo case; the available literature consists of general guidelines or unrelated clinical guidance.
Still missing
  • A published or clinical case observation involving the exact variant
  • Proband phenotype and family-history information
  • Parental genotyping or a documented unconfirmed de novo claim
Sources
clinvar ↗PMID:25394175 ↗PMID:25741868 ↗
PP1 Not assessed: no affected relatives, informative meioses, or genotype-phenotype segregation results are documented. Details ▾Hide ▴
Reasoning

PP1 cannot be assessed because no affected or unaffected relatives, informative meioses, genotype-phenotype correlations, or family segregation results are documented for NM_006231.4:c.2113C>T (NP_006222.2:p.Arg705Trp). The available ClinVar record contains no family segregation evidence. The local POLE framework does not specify PP1, so generic ACMG/AMP criteria apply.

Rule
Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members; strength depends on the number and informativeness of meioses, none of which are documented.
Evidence considered
  • ClinVar variation 540760 provides no documented pedigree, affected-relative testing, unaffected-relative testing, or segregation count for the exact variant.
  • The available paper extractions do not report the exact variant or any POLE family segregation study.
Still missing
  • Pedigree and number of informative meioses
  • Genotypes of affected relatives
  • Genotypes and phenotypes of unaffected relatives
  • Phenotype consistency with the relevant POLE-associated disorder
Sources
clinvar ↗PMID:25394175 ↗PMID:25741868 ↗
PP4 Not assessed: no patient-level phenotype or disease-specific clinical feature set is available to evaluate PP4. Details ▾Hide ▴
Reasoning

No patient-level phenotype, clinical presentation, or disease-specific feature set is provided for this case. ClinVar condition labels are database metadata and do not establish a phenotype-specific match for the individual. Consequently, the disease-specific phenotype evidence required for PP4 cannot be assessed.

Rule
Assess PP4 only when the patient's phenotype or disease-specific clinical features are sufficiently specific for the gene-associated condition.
Evidence considered
  • The reviewed case materials provide variant normalization and database records but no individual clinical phenotype or disease-specific presentation.
  • ClinVar lists condition labels including colorectal cancer susceptibility and hereditary cancer-predisposing syndrome, but these labels are not patient-level phenotype evidence.
Still missing
  • Patient phenotype and clinical diagnosis are not available in the reviewed case materials.
BS3 Not assessed: no variant-specific validated functional assay, controls, or normal-function readout were documented for p.Arg705Trp. Details ▾Hide ▴
Reasoning

No variant-specific validated functional assay is documented for NM_006231.4:c.2113C>T (NP_006222.2:p.Arg705Trp). The available POLE framework does not specify BS3, and the reviewed evidence contains no assay demonstrating preserved normal function with appropriate controls, validated biological relevance, or quantitative benign functional results. OncoKB reports no variant-specific reviewed functional evidence. BS3 therefore cannot be assigned.

Evidence considered
  • OncoKB reports no variant-specific reviewed functional evidence for POLE p.Arg705Trp.
  • The reviewed ACMG/AMP guidance provides general functional-evidence principles but reports no POLE-specific assay or result for this variant.
  • The local POLE framework customizes PM1, PS4, PP3, and BP4 only; it provides no BS3 specification.
Still missing
  • A biologically relevant, validated functional assay for p.Arg705Trp demonstrating preserved normal function with appropriate controls is needed.
  • Quantitative assay results and laboratory validation details are unavailable.
Sources
oncokb ↗PMID:25741868 ↗
BS4 Not assessed: no informative unaffected-relative testing or documented non-segregation is available for this variant. Details ▾Hide ▴
Reasoning

BS4 cannot be assessed because no unaffected relatives known to be non-carriers, no affected relatives known to lack the variant, and no informative family testing are documented for NM_006231.4:c.2113C>T (NP_006222.2:p.Arg705Trp). Absence of family data is not evidence of non-segregation. The local POLE framework does not specify BS4, so generic ACMG/AMP criteria apply.

Rule
Generic ACMG/AMP BS4: lack of segregation in affected family members or presence in unaffected individuals when the phenotype is expected to be penetrant; no qualifying evidence is documented.
Evidence considered
  • ClinVar variation 540760 contains no documented family testing or non-segregation observation for the exact variant.
  • No reviewed publication extraction reports an informative POLE family in which the variant fails to segregate with disease.
Still missing
  • Family pedigree with phenotypic status
  • Genotyping of informative affected and unaffected relatives
  • Evidence that the variant fails to track with disease
Sources
clinvar ↗PMID:25394175 ↗PMID:25741868 ↗
BP2 Not assessed: no linked pathogenic variant or phase-resolved cis observation is available to evaluate BP2. Details ▾Hide ▴
Reasoning

BP2 cannot be assessed because the available evidence contains no observation of this variant in cis with a pathogenic or likely pathogenic variant, and no phase-resolved unaffected-individual or family observation relevant to a benign allelic configuration. The case materials do not report linked variants, parental testing, haplotypes, or segregation. The available POLE-specific framework does not specify BP2, and the reviewed literature extracts contain no variant-specific cis-phase evidence.

Evidence considered
  • No case-level linked-variant, cis-phase, parental, haplotype, or segregation evidence for NM_006231.4:c.2113C>T (NP_006222.2:p.(Arg705Trp)) is present in the supplied case materials.
  • The local POLE framework specifies PM1, PS4, PP3, and BP4 only; it provides no POLE-specific BP2 rule.
  • The extracted reviewed publications contain no variant-specific cis-phase or allelic observations for this variant.
Still missing
  • A pathogenic or likely pathogenic variant observed with this variant
  • Validated cis phase between the two variants
  • Relevant unaffected-individual or family segregation data
BP5 Not assessed: no affected individual with a documented alternative pathogenic molecular explanation is reported in the available case evidence. Details ▾Hide ▴
Reasoning

No qualifying evidence shows that this variant occurs in an affected individual who has an alternative pathogenic molecular explanation for the relevant phenotype. The available ClinVar record contains non-expert uncertain-significance submissions, not a documented alternative pathogenic explanation for a specific patient. BP5 therefore cannot be assessed from the available case evidence.

Rule
Assess BP5 only when the variant is observed in an affected individual with a convincing alternative pathogenic molecular explanation for the phenotype under evaluation.
Evidence considered
  • The available case materials contain no patient-level co-occurring pathogenic variant or alternative molecular diagnosis suitable for BP5.
  • ClinVar records non-expert Uncertain significance submissions and does not provide a documented alternative pathogenic explanation for an affected individual.
Still missing
  • No patient-level report establishes an alternative pathogenic variant or molecular diagnosis for the relevant phenotype.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: NM_006231.4:c.2113C>T is a missense variant, p.Arg705Trp, not a nonsense, frameshift, or canonical splice loss-of-function variant. Details ▾Hide ▴
Reasoning

No applicable POLE-specific PVS1 specification was identified, so the generic ClinGen SVI framework applies. NM_006231.4:c.2113C>T is a missense substitution producing NP_006222.2:p.(Arg705Trp), not a nonsense, frameshift, or canonical ±1,2 splice-site variant. The generic PVS1 null-variant gate therefore does not apply; there is no premature termination, established NMD substrate, exon-skipping consequence, or protein-length loss to assess. This is not a downgraded PVS1 call: PVS1 is not applicable to the documented missense consequence.

Rule
Generic ClinGen SVI PVS1 null-variant eligibility gate
Evidence considered
  • The normalized consequence is missense: NM_006231.4:c.2113C>T, NP_006222.2:p.(Arg705Trp).
  • The generic ClinGen SVI PVS1 framework limits PVS1 assessment to qualifying loss-of-function/null-variant mechanisms; this variant is outside the applicable nonsense, frameshift, and canonical splice-site categories.
  • The variant assessment records no exon-skipping or canonical splice-consensus consequence and explicitly identifies the variant as outside the default generic PVS1 null-variant buckets.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM4 N/ANot applicable: p.Arg705Trp is a missense substitution with no amino-acid insertion, deletion, or protein-length change. Details ▾Hide ▴
Reasoning

No applicable POLE-specific PM4 specification was identified, so the generic ACMG/AMP definition applies. PM4 concerns an abnormal protein-length change caused by an in-frame deletion or insertion, or another established protein-length-altering consequence. NM_006231.4:c.2113C>T is a single-nucleotide missense substitution yielding p.Arg705Trp; it neither inserts nor deletes amino acids and does not change the encoded protein length. PM4 is therefore not applicable.

Rule
Generic ACMG/AMP PM4: abnormal protein length due to in-frame insertion or deletion
Evidence considered
  • The normalized variant consequence is a single-nucleotide missense substitution, NM_006231.4:c.2113C>T, p.Arg705Trp.
  • Because the available POLE framework customizes other criteria and does not specify PM4, the generic ACMG/AMP PM4 definition is used.
  • A missense substitution does not produce the in-frame insertion, deletion, or other protein-length alteration required for PM4.
Sources
generic_acmg_combination_rulespvs1_variant_assessment
BP3 N/ANot applicable: p.Arg705Trp is not an in-frame insertion or deletion in a repetitive region and has no repeat-associated protein-length alteration. Details ▾Hide ▴
Reasoning

No applicable POLE-specific BP3 specification was identified, so the generic ACMG/AMP definition applies. BP3 is intended for in-frame insertions or deletions in a repetitive region without a known function. NM_006231.4:c.2113C>T is a missense substitution producing p.Arg705Trp, with no in-frame insertion or deletion and no repeat-associated protein-length alteration. BP3 is therefore not applicable.

Rule
Generic ACMG/AMP BP3: in-frame indel in a repetitive region without known function
Evidence considered
  • The normalized variant consequence is missense, not an in-frame insertion or deletion: NM_006231.4:c.2113C>T, p.Arg705Trp.
  • Because the available POLE framework does not specify BP3, the generic ACMG/AMP BP3 definition is used.
  • The documented consequence provides no repeat-region in-frame indel or protein-length change to which BP3 could apply.
Sources
generic_acmg_combination_rulespvs1_variant_assessment
BP7 N/ANot applicable: c.2113C>T is missense and changes p.Arg705 to Trp, whereas BP7 applies only to synonymous variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous variants. NM_006231.4:c.2113C>T is a missense variant resulting in p.Arg705Trp/p.R705W, so BP7 is outside scope and no synonymous-variant computational assessment is applicable.

Rule
BP7 applies only to synonymous variants.
Evidence considered
  • The case consequence is missense: NM_006231.4:c.2113C>T, NP_006222.2:p.(Arg705Trp)/p.(R705W).

Identifiers

Gene
POLE
Transcript
NM_006231.4
Coding (HGVS c.)
NM_006231.4:c.2113C>T
Protein (HGVS p.)
NP_006222.2:p.(Arg705Trp)
GRCh38
chr12:132668416 G>A
GRCh37
chr12:133245002 G>A
Location and type
Exon 19 · missense
ClinVar
540760
COSMIC
COSV57693351

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…
gnomAD v4.1 9 / 1,612,610 alleles AF 5.58e-06 · 0 homozygotes · FAF 1.83e-06
gnomAD v2.1 4 / 281,598 alleles AF 1.42e-05 · 0 homozygotes · FAF 2.24e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 5.6e-06 · 9 / 1,612,610 alleles · 0 hom · FAF 1.8e-06
East Asian1 / 44,832 2.2e-05
Admixed American1 / 59,776 1.7e-05
South Asian1 / 90,866 1.1e-05
European (non-Finnish)6 / 1,179,258 5.1e-06
0 alternate alleles recorded in 6 other groups: Remaining individuals, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 1.4e-05 · 4 / 281,598 alleles · 0 hom · FAF 2.2e-05
East Asian1 / 19,838 5e-05
Admixed American1 / 35,190 2.8e-05
European (non-Finnish)2 / 128,692 1.6e-05
0 alternate alleles recorded in 5 other groups: African/African American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 5.58101e-06; MAF= 0.00056%, 9/1612610 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23055e-05; MAF= 0.00223%, 1/44832 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.42046e-05; MAF= 0.00142%, 4/281598 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.04083e-05; MAF= 0.00504%, 1/19838 alleles, homozygotes = 0); grpmax FAF= 2.242e-05.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +11 bp
0.027
SpliceAI acceptor gainat +80 bp
0.003
SpliceAI donor lossat +174 bp
0.002
SpliceAI donor gainat +178 bp
0.001
Pangolin splice lossmagnitude shown
-0.008
Pangolin splice gain
0.001

Other predictors

REVEL
0.321
BayesDel
0.058

How the predictions were used

PP3 Not met: REVEL 0.321 is below the generic PP3 supporting threshold of 0.644 and the POLE table labels p.R705W Likely benign, not likely disease causing. Details ▾Hide ▴
Reasoning

The variant is missense (NM_006231.4:c.2113C>T, p.Arg705Trp/p.R705W), so the applicable computational path is REVEL only. The governing POLE supplementary Table S2 contains the exact p.R705W entry and pre-assigns REVEL class 'Likely benign' with 1 benign in-silico result; therefore the POLE custom PP3 rule (REVEL class likely disease causing and no more than 1 benign result) is not satisfied. The independent REVEL score is 0.321, below the supplied generic PP3 supporting threshold of 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). The SpliceAI max delta of 0.027 was not used because splice predictions cannot support PP3 for a missense variant. The exact variant was found in PATH-250-323.pdf and PATH-250-323-s002.xlsx, but those entries are contextual somatic/recurrent-variant material rather than a PP3-triggering computational assignment. No exact variant entry was found in PATH-250-323-s004.xlsx.

Rule
Missense variant: use REVEL only. POLE custom PP3 supporting requires exact presence in Supplementary Table S2 or S3, REVEL class likely disease causing, and no more than 1 benign in-silico result; otherwise generic PP3 supporting requires REVEL >= 0.644.
Evidence considered
  • PATH-250-323-s003.xlsx, Supplementary Table S2, exact p.R705W/c.2113C>T row: REVEL class 'Likely benign' and 1 benign result; this does not meet the POLE custom PP3 rule requiring likely disease causing and no more than 1 benign result.
  • Local REVEL score is 0.321, below the supplied generic PP3 supporting cutoff of 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
  • PATH-250-323.pdf contains the exact c.2113C>T entry, and PATH-250-323-s002.xlsx contains the exact p.R705W/c.2113C>T entry; these were reviewed as contextual/recurrent-variant material, not as a PP3-triggering computational assignment.
  • PATH-250-323-s004.xlsx was searched for c.2113C>T, p.Arg705Trp, and p.R705W; no exact entry was found.
  • SpliceAI max delta 0.027 was not used for this missense variant because PP3/BP4 evidence must come from the consequence-matched REVEL path.
Still missing
  • No exact c.2113C>T, p.Arg705Trp, or p.R705W entry was found in PATH-250-323-s004.xlsx; this is a table-specific negative search result, not evidence that computational evidence is absent.
Sources
vcep_path_250_323_s003revel
BP4 Not met: REVEL 0.321 exceeds the generic BP4 supporting threshold of 0.29, while the POLE table reports only 1 benign result versus the required 4. Details ▾Hide ▴
Reasoning

The variant is missense, so the applicable computational path is REVEL only. The governing POLE supplementary Table S2 contains the exact p.R705W entry and pre-assigns REVEL class 'Likely benign' with 1 benign in-silico result; the POLE custom BP4 rule requires REVEL class Likely benign plus at least 4 benign results, so it is not satisfied. The independent REVEL score is 0.321, above the supplied generic BP4 supporting threshold of 0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997), so generic BP4 is also not met. The SpliceAI max delta of 0.027 was not used because splice predictions cannot provide BP4 for a missense variant. No exact variant entry was found in PATH-250-323-s004.xlsx.

Rule
Missense variant: use REVEL only. POLE custom BP4 supporting requires exact presence in Supplementary Table S2 or S3, REVEL class Likely benign, and at least 4 benign in-silico results; otherwise generic BP4 supporting requires REVEL <= 0.29.
Evidence considered
  • PATH-250-323-s003.xlsx, Supplementary Table S2, exact p.R705W/c.2113C>T row: REVEL class 'Likely benign' but only 1 benign result; this does not meet the POLE custom BP4 rule requiring at least 4 benign results.
  • Local REVEL score is 0.321, above the supplied generic BP4 supporting cutoff of 0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
  • PATH-250-323-s004.xlsx was searched for c.2113C>T, p.Arg705Trp, and p.R705W; no exact entry was found.
  • SpliceAI max delta 0.027 was not used for this missense variant because BP4 evidence must come from the consequence-matched REVEL path.
Still missing
  • No exact c.2113C>T, p.Arg705Trp, or p.R705W entry was found in PATH-250-323-s004.xlsx; this is a table-specific negative search result, not evidence that computational evidence is absent.
Sources
vcep_path_250_323_s003revel
BP7 N/ANot applicable: c.2113C>T is missense and changes p.Arg705 to Trp, whereas BP7 applies only to synonymous variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous variants. NM_006231.4:c.2113C>T is a missense variant resulting in p.Arg705Trp/p.R705W, so BP7 is outside scope and no synonymous-variant computational assessment is applicable.

Rule
BP7 applies only to synonymous variants.
Evidence considered
  • The case consequence is missense: NM_006231.4:c.2113C>T, NP_006222.2:p.(Arg705Trp)/p.(R705W).

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.321. BayesDel score = 0.0580204.

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    Richards S et al. · 2015
    This paper provides general ACMG/AMP variant-interpretation guidance but does not mention POLE or the exact c.2113C>T (p.Arg705Trp) variant and reports no variant-specific proband, parental, segregation, or non-segregation evidence.
    Does not name this variant
    PMID 25741868 ↗
    Quoted passage
    The impact of a missense change depends on criteria such as the evolutionary conservation of an amino acid or nucleotide, the location and context within the protein sequence, and the biochemical consequence of the amino acid substitution.

    Computational (In Silico) Predictive Programs

  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    This paper is a practice guideline describing indications for referral for cancer predisposition assessment. It does not report POLE, the exact c.2113C>T variant, the p.Arg705Trp change, or any variant-specific proband, parental, segregation, or non-segregation data.
    Does not name this variant
    PMID 25394175 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 9 / 1,612,610 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.027 Open source ↗
ClinVar 5 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB 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= 5.58101e-06; MAF= 0.00056%, 9/1612610 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.23055e-05; MAF= 0.00223%, 1/44832 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.42046e-05; MAF= 0.00142%, 4/281598 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.04083e-05; MAF= 0.00504%, 1/19838 alleles, homozygotes = 0); grpmax FAF= 2.242e-05.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 540760)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.321. BayesDel score = 0.0580204.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high m

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57693351, n = 4 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.