POLE c.4960C>T, p.His1654Tyr
NM_006231.4:c.4960C>T
Variant of Uncertain Significance (VUS)
Classified as Variant of Uncertain Significance based on PM2 (absent from controls) and BP4 (benign computational predictions); insufficient evidence for pathogenic or benign classification.
ACMG/AMP Criteria Applied
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
POLE
Transcript
NM_006231.4
MANE Select
Total Exons
49
Strand
Reverse (−)
Reference Sequence
NC_000012.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_006231.2 | Alternative | 49 exons | Reverse |
| NM_006231.3 | RefSeq Select | 49 exons | Reverse |
Variant Details
HGVS Notation
NM_006231.4:c.4960C>T
Protein Change
H1654Y
Location
Exon 38
(Exon 38 of 49)
5'Exon Structure (49 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1654 in gene POLE
Variant interpretation based on transcript NM_006231.4
Genome Browser
Loading genome browser...
HGVS InputNM_006231:c.4960C>T
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 1654 in gene POLE
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.467
0.467
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 4.69metasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function is a known mechanism of disease". The evidence for this variant shows: H1654Y is a missense variant, not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not a null (LoF) change.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". The evidence for this variant shows: no known pathogenic variant with the same H1654Y amino acid change. Therefore, this criterion is not applied at Not Applied strength because there is no established pathogenic variant at this residue.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo testing or parental confirmation data are available. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be assessed.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies have been performed on H1654Y. Therefore, this criterion is not applied at Not Applied strength because functional data are lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control or cohort data demonstrating enrichment in affected individuals. Therefore, this criterion is not applied at Not Applied strength because prevalence data are unavailable.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: H1654 is not described as a known hotspot or critical functional residue. Therefore, this criterion is not applied at Not Applied strength because the variant is not in a recognized hotspot or functional domain.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: H1654Y is not found in gnomAD, 1000 Genomes, or other population databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from control populations.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no information on phase with any pathogenic variant. Therefore, this criterion is not applied at Not Applied strength because trans configuration data are not available.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: H1654Y is a missense change with no length alteration. Therefore, this criterion is not applied at Not Applied strength because there is no change in protein length.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no pathogenic missense variants reported at residue H1654. Therefore, this criterion is not applied at Not Applied strength because no other pathogenic variant is known at this site.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied at Not Applied strength because de novo status cannot be assumed.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation information is unavailable.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: insufficient data on POLE’s missense tolerance and mechanism. Therefore, this criterion is not applied at Not Applied strength because gene-level missense constraints are not established.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: computational tools predict benign impact (CADD, MetaSVM, MetaLR, PrimateAI) and SpliceAI score 0.02. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support deleteriousness.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype or family history data provided. Therefore, this criterion is not applied at Not Applied strength because phenotype specificity cannot be assessed.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: not reported in ClinVar or other reputable databases. Therefore, this criterion is not applied at Not Applied strength because no external pathogenic assertions exist.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (stand-alone benign)". The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied at Not Applied strength because the frequency is not above threshold.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder". The evidence for this variant shows: allele frequency is 0% in controls. Therefore, this criterion is not applied at Not Applied strength because frequency does not exceed disease expectation.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age". The evidence for this variant shows: no healthy adult observation data. Therefore, this criterion is not applied at Not Applied strength because no such observations exist.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied at Not Applied strength because functional data are absent.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength because segregation information is unavailable.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease". The evidence for this variant shows: disease mechanism for POLE involves missense changes in proofreading domain. Therefore, this criterion is not applied at Not Applied strength because missense variants are a known mechanism.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no phase data with other variants. Therefore, this criterion is not applied at Not Applied strength because phase information is absent.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: H1654Y is a missense change, not an in-frame indel. Therefore, this criterion is not applied at Not Applied strength because it is not an in-frame indel.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: CADD, MetaSVM, MetaLR, PrimateAI predict benign, REVEL score 0.47 below pathogenic threshold, and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because computational analyses consistently predict no deleterious effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no case reports with an alternate molecular diagnosis. Therefore, this criterion is not applied at Not Applied strength because no such case data exist.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: not reported in ClinVar or other databases as benign. Therefore, this criterion is not applied at Not Applied strength because no external benign assertions exist.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: H1654Y is a missense change, not synonymous. Therefore, this criterion is not applied at Not Applied strength because it is not a synonymous variant.