POLE c.6135C>T, p.Pro2045=
NM_006231.4:c.6135C>T
COSMIC ID: COSM7218235
Variant of Uncertain Significance (VUS)
This synonymous POLE variant is extremely rare (PM2), with multiple computational tools predicting no impact on splicing or protein function (BP4, BP7), and lacks functional, segregation, or clinical data. The evidence is insufficient to classify as benign or pathogenic, resulting in a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP4
BP7
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.6135C>T
Protein Change
P2045=
Location
Exon 44
(Exon 44 of 49)
5'Exon Structure (49 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM7218235
Variant interpretation based on transcript NM_006231.4
Genome Browser
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HGVS InputNM_006231:c.6135C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0078%
Rare
Highest in Population
East Asian
0.0301%
Low Frequency
Global: 0.0078%
East Asian: 0.0301%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 281970Alt: 22Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0078%, 22/281970 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.0301%, 6/19938 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 7 submitter reviews in ClinVar
Submitter Breakdown
2 VUS
5 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely benign (5 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.53
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PVS1 rule is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion) in a gene where loss of function is a known mechanism of disease." The evidence for this variant shows: it is a synonymous variant (P2045=) with no disruption of the coding sequence or canonical splice sites. Therefore, this criterion is not applied because the variant is not a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PS1 rule is: "Same amino acid change as a known pathogenic variant but different nucleotide change." The evidence for this variant shows: it is a synonymous change (no amino acid change). Therefore, this criterion is not applied because there is no amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PS2 rule 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 information on de novo occurrence or parental genotypes. Therefore, this criterion is not applied due to lack of de novo data.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PS3 rule 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. Therefore, this criterion is not applied because functional evidence is absent.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PS4 rule is: "Prevalence in affected individuals significantly increased compared with controls." The evidence for this variant shows: no case–control or segregation data demonstrating increased prevalence in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM1 rule is: "Located in a mutational hot spot or well‐established functional domain without benign variation." The evidence for this variant shows: no data indicating location in a known hotspot or functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the PM2 rule is: "Absent from controls (or at extremely low frequency if recessive)." The evidence for this variant shows: MAF = 0.0078% in gnomAD (22/281,970 alleles), with no homozygotes. Therefore, this criterion is applied at Moderate strength because the variant is absent or extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM3 rule is: "Detected in trans with a pathogenic variant for recessive disorders." The evidence for this variant shows: no data on allelic phase or recessive inheritance context. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM4 rule is: "Protein length changes due to in‐frame deletions/insertions or stop‐loss variants." The evidence for this variant shows: it is synonymous with no change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM5 rule is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen." The evidence for this variant shows: it is synonymous, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PM6 rule is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no data suggesting de novo occurrence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP1 rule is: "Co‐segregation with disease in multiple affected family members." The evidence for this variant shows: no familial segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP2 rule 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: it is synonymous, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP3 rule is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product." The evidence for this variant shows: in silico predictors are benign (CADD = –0.53, SpliceAI = 0.02). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP4 rule 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 clinical data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the PP5 rule is: "Reputable source reports variant as pathogenic, but without accessible evidence." The evidence for this variant shows: no reputable source reports it as pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BA1 rule is: "Allele frequency is too high for the disorder (stand‐alone benign)." The evidence for this variant shows: MAF = 0.0078%, well below the BA1 threshold of >5%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS1 rule is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: MAF is below disease‐specific thresholds. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS2 rule 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 specific data on healthy carriers with confirmed health status. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS3 rule 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.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BS4 rule is: "Lack of segregation in affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP1 rule is: "Missense variant in a gene where only loss of function causes disease." The evidence for this variant shows: it is synonymous, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP2 rule 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 phase data with other variants. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP3 rule is: "In‐frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is synonymous, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the BP4 rule is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: CADD = –0.53, SpliceAI = 0.02, and other in silico tools predict no effect. Therefore, this criterion is applied at Supporting strength because computational evidence indicates no impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP5 rule is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no reports of the variant in cases with another molecular diagnosis. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the BP6 rule is: "Reputable source reports variant as benign, but without accessible evidence." The evidence for this variant shows: no detailed benign assertion without evidence. ClinVar reports likely benign but evidence is accessible. Therefore, this criterion is not applied.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the BP7 rule is: "Synonymous variant with no predicted impact on splicing and no conservation of the nucleotide." The evidence for this variant shows: it is synonymous and SpliceAI = 0.02 predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because it is a silent change with no splicing effect.