POLE c.889T>C, p.Ser297Pro
NM_006231.4:c.889T>C
Variant of Uncertain Significance (VUS)
This legacy system is being phased out as Project HERA V3 is rolled out.
ACMG/AMP Criteria Applied
PM2
PM5
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.889T>C
Protein Change
S297P
Location
Exon 9
(Exon 9 of 49)
5'Exon Structure (49 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 297 in gene POLE
Variant interpretation based on transcript NM_006231.4
Genome Browser
Loading genome browser...
HGVS InputNM_006231:c.889T>C
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 297 in gene POLE
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingprimateai: D
Benign:
CADD: 5.39metasvm: 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/finding for PVS1 is: 'PVS1 – Null variant in a gene where loss of function (LoF) is a known mechanism of disease'. The evidence for this variant shows: this is a missense change (S297P), not a null variant. Therefore, this criterion is Not Applied because the variant type is not a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS1 is: 'PS1 – Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: there is no previously established pathogenic variant with the same amino acid change at codon 297. Therefore, this criterion is Not Applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS2 is: 'PS2 – De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: there are no data on de novo occurrence. Therefore, this criterion is Not Applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS3 is: 'PS3 – 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 reported. Therefore, this criterion is Not Applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS4 is: 'PS4 – Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case-control or cohort data are available. Therefore, this criterion is Not Applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM1 is: 'PM1 – Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: residue S297 is not reported as a mutational hotspot or within a characterized critical domain devoid of benign variation. Therefore, this criterion is Not Applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule/finding for PM2 is: 'PM2 – Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: it is not found in gnomAD, 1000 Genomes, or ExAC. Therefore, this criterion is Applied at Moderate strength because the variant is absent from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM3 is: 'PM3 – Detected in trans with a pathogenic variant (for recessive disorders)'. The evidence for this variant shows: no data on phase or recessive compound heterozygosity. Therefore, this criterion is Not Applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM4 is: 'PM4 – Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: it is a missense change with no alteration of protein length. Therefore, this criterion is Not Applied.
PM5
PM5 (Moderate)
According to standard ACMG guidelines, the rule/finding for PM5 is: 'PM5 – Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: other pathogenic missense variants at residue S297 have been reported. Therefore, this criterion is Applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM6 is: 'PM6 – Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no de novo assumption data. Therefore, this criterion is Not Applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP1 is: 'PP1 – Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no segregation data available. Therefore, this criterion is Not Applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP2 is: 'PP2 – 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 the rate of benign versus pathogenic missense variation in POLE. Therefore, this criterion is Not Applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP3 is: 'PP3 – Multiple lines of computational evidence support a deleterious effect on the gene/gene product'. The evidence for this variant shows: computational predictions are mixed, with a preponderance of benign predictions and no splicing impact. Therefore, this criterion is Not Applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP4 is: 'PP4 – 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.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP5 is: 'PP5 – Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: no such reports in ClinVar or other databases. Therefore, this criterion is Not Applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BA1 is: 'BA1 – Allele frequency is too high for the disorder'. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is Not Applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS1 is: 'BS1 – Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is Not Applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS2 is: 'BS2 – 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.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS3 is: 'BS3 – Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: no functional studies. Therefore, this criterion is Not Applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS4 is: 'BS4 – 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 rule/finding for BP1 is: 'BP1 – Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: POLE pathogenic variants are often missense in the exonuclease domain, not exclusively LoF. Therefore, this criterion is Not Applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP2 is: 'BP2 – Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no cis/trans data. Therefore, this criterion is Not Applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP3 is: 'BP3 – In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: it is a missense change, not an in-frame indel. Therefore, this criterion is Not Applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule/finding for BP4 is: 'BP4 – Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows: multiple benign in silico predictions and no predicted splicing impact by SpliceAI. Therefore, this criterion is Applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP5 is: 'BP5 – Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no such case data. Therefore, this criterion is Not Applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP6 is: 'BP6 – Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: no such reports. Therefore, this criterion is Not Applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP7 is: 'BP7 – Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: it is a missense variant. Therefore, this criterion is Not Applied.