POLE c.777C>T, p.Arg259=
NM_006231.4:c.777C>T
Likely Benign
This POLE c.777C>T (R259=) synonymous variant is absent from population databases, predicted benign by computational tools with no splicing impact, and reported as Likely Benign in ClinVar. Applying PM2 (Moderate), BP4, BP6, and BP7 (Supporting), the aggregate evidence supports a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BP4
BP6
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.777C>T
Protein Change
R259=
Location
Exon 8
(Exon 8 of 49)
5'Exon Structure (49 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_006231.4
Genome Browser
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HGVS InputNM_006231:c.777C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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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
Likely Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.64
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: NM_006231.4:c.777C>T is a synonymous change (R259=) that does not introduce a stop codon or alter splice sites. Therefore, this criterion is not applied at Not Applied strength because the variant does not produce a null effect.
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: It is synonymous and does not change the amino acid. Therefore, this criterion is not applied at Not Applied strength because there is no 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 de novo testing or family history data are available. Therefore, this criterion is not applied at Not Applied strength because de novo occurrence has not been 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. Therefore, this criterion is not applied at Not Applied strength because functional impact has not been experimentally evaluated.
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 data or disease prevalence studies are available. Therefore, this criterion is not applied at Not Applied strength because case‐control enrichment has not been assessed.
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: It is a synonymous change outside of known domains. Therefore, this criterion is not applied at Not Applied strength because it does not affect a critical domain or hotspot.
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: It is not found in gnomAD or other population databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from large control cohorts.
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 data on phasing or trans occurrences. Therefore, this criterion is not applied at Not Applied strength because compound heterozygosity has not been assessed.
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 synonymous substitution with no impact on 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: It is synonymous and does not change the amino acid. Therefore, this criterion is not applied at Not Applied strength because there is no missense change.
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 assessment data are available. Therefore, this criterion is not applied at Not Applied strength because unconfirmed 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 analysis is not available.
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: It is synonymous. Therefore, this criterion is not applied at Not Applied strength because it is not a missense change.
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: In silico tools predict no deleterious effect and SpliceAI score is zero. Therefore, this criterion is not applied at Not Applied strength because computational evidence does not support pathogenicity.
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 patient phenotype 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: ClinVar reports Likely Benign, not pathogenic. Therefore, this criterion is not applied at Not Applied strength because no reputable source reports it as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder (based on population data)'. The evidence for this variant shows: It is absent from population databases. Therefore, this criterion is not applied at Not Applied strength because the variant frequency is not high.
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: It is absent from gnomAD. Therefore, this criterion is not applied at Not Applied strength because the allele frequency is not elevated.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in healthy individuals with full penetrance expected at an early age'. The evidence for this variant shows: No data on observation in healthy individuals. Therefore, this criterion is not applied at Not Applied strength because cohort data in unaffected individuals are not available.
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 assays conducted. Therefore, this criterion is not applied at Not Applied strength because functional evidence is lacking.
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 data. Therefore, this criterion is not applied at Not Applied strength because family studies are not available.
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: It is synonymous. Therefore, this criterion is not applied at Not Applied strength because the variant is not missense.
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 phasing or compound data. Therefore, this criterion is not applied at Not Applied strength because cis/trans relationships are unknown.
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: It is a single-nucleotide synonymous change, not an 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 the gene/gene product'. The evidence for this variant shows: In silico tools are benign and SpliceAI predicts no splicing impact (score=0). Therefore, this criterion is applied at Supporting strength because computational analyses uniformly indicate no functional 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 alternate diagnoses. Therefore, this criterion is not applied at Not Applied strength because case context is unavailable.
BP6
BP6 (Supporting)
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: ClinVar lists it as Likely Benign from one clinical laboratory. Therefore, this criterion is applied at Supporting strength because a reputable database classifies it as benign without available primary evidence.
BP7
BP7 (Supporting)
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 synonymous substitution and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because it meets the criteria for a silent change with no splicing effect.