POLE c.2510T>C, p.Phe837Ser
NM_006231.4:c.2510T>C
Variant of Uncertain Significance (VUS)
The variant NM_006231.4:c.2510T>C (p.F837S) in POLE is classified as a Variant of Uncertain Significance due to the combination of moderate population rarity (PM2) and supporting benign computational evidence (BP4), with insufficient evidence from other criteria to reach a definitive 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.2510T>C
Protein Change
F837S
Location
Exon 22
(Exon 22 of 49)
5'Exon Structure (49 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 837 in gene POLE
Variant interpretation based on transcript NM_006231.4
Genome Browser
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HGVS InputNM_006231:c.2510T>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0269%
Low Frequency
Highest in Population
Ashkenazi Jewish
0.453%
Common
Global: 0.0269%
Ashkenazi Jewish: 0.453%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282762Alt: 76Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0269%, 76/282762 alleles, homozygotes = 0) and at a higher frequency in the Ashkenazi Jewish population (MAF= 0.453%, 47/10368 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
7 VUS
2 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratories).
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 837 in gene POLE
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.116
0.116
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
Pathogenic:
primateai: D
Benign:
CADD: 3.53polyphen_prediction: benignmetasvm: Tmetalr: 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 (LoF) is a known mechanism of disease'. The evidence for this variant shows: it is a missense change (F837S), not a null variant. Therefore, this criterion is not applied at Not Applied strength because the variant is not a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: no previously established pathogenic variant causing the same F837S change. Therefore, this criterion is not applied at Not Applied strength because there is no matching pathogenic amino acid change.
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 parental testing or de novo status data available. Therefore, this criterion is not applied at Not Applied strength because de novo occurrence has not been demonstrated.
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 POLE F837S. Therefore, this criterion is not applied at Not Applied strength because there are no functional study data.
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 prevalence data in affected cohorts. Therefore, this criterion is not applied at Not Applied strength because increased prevalence in cases has not been demonstrated.
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: no evidence that F837 lies in a mutational hotspot or a critical functional domain. Therefore, this criterion is not applied at Not Applied strength because the variant is not in a recognized hotspot or 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: MAF=0.0269% in gnomAD (76/282,762 alleles), extremely rare. Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency in population databases.
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 phasing or trans configuration. Therefore, this criterion is not applied at Not Applied strength because trans configuration with a pathogenic variant is not known.
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: it is a missense change without alteration of protein length. 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 other pathogenic missense changes reported at residue F837. Therefore, this criterion is not applied at Not Applied strength because no pathogenic variant at the same residue is known.
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 data on de novo occurrence. Therefore, this criterion is not applied at Not Applied strength because de novo status is not assessed.
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 has not been evaluated.
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 missense constraint and disease mechanism. Therefore, this criterion is not applied at Not Applied strength because the gene-specific missense context is unclear.
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 (REVEL 0.12, CADD, PolyPhen-2, MetaSVM, MetaLR) predict benign impact. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support deleterious effect.
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 clinical phenotype or family history provided. Therefore, this criterion is not applied at Not Applied strength because phenotype data are lacking.
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: no reputable source reports this variant as pathogenic. Therefore, this criterion is not applied at Not Applied strength because no pathogenic reputation exists.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder'. The evidence for this variant shows: MAF=0.0269%, well below >5% threshold. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is not above the stand-alone threshold.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: MAF=0.0269% is not above the expected threshold for POLE-related disease. Therefore, this criterion is not applied at Not Applied strength because frequency is not higher than expected.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy adult individuals for a dominant disorder with full penetrance expected at an early age'. The evidence for this variant shows: heterozygotes observed in gnomAD but no data on health status or penetrance. Therefore, this criterion is not applied at Not Applied strength because healthy carrier status cannot be confirmed.
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 available. Therefore, this criterion is not applied at Not Applied strength because functional effect has not been tested.
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 segregation analysis. Therefore, this criterion is not applied at Not Applied strength because family segregation 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 LoF causes disease'. The evidence for this variant shows: POLE disease mechanism is not solely loss-of-function. Therefore, this criterion is not applied at Not Applied strength because missense variants can be disease-causing.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant'. The evidence for this variant shows: no information on co-occurrence with other variants. Therefore, this criterion is not applied at Not Applied strength because phasing data are not available.
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: this is a missense change. 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: REVEL score 0.12 (<0.15 threshold), CADD, PolyPhen-2, MetaSVM, MetaLR predict benign impact, SpliceAI 0.06 indicates minimal splicing effect. Therefore, this criterion is applied at Supporting strength because multiple computational tools predict a benign 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 genetic diagnosis. Therefore, this criterion is not applied at Not Applied strength because no alternate molecular basis is documented.
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: while some ClinVar submissions list likely benign or benign, accessible supporting evidence is lacking. Therefore, this criterion is not applied at Not Applied strength because detailed benign evidence is not available.
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: it is a missense change, not synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not synonymous.