Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_006231.4 | MANE Select | 7823 nt | 28–6888 |
| NM_006231.2 | Alternative | 7859 nt | 45–6905 |
| NM_006231.3 | RefSeq Select | 8024 nt | 210–7070 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 88 bp |
| Donor Loss (DL) | 0.04 | -2 bp |
| Acceptor Gain (AG) | 0.0 | -354 bp |
| Donor Gain (DG) | 0.02 | -5 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease'. The evidence for this variant shows: the variant is a missense change (T1771M) and does not introduce a premature stop codon or affect canonical splice sites. Therefore, this criterion is not applied because the variant type is not a null variant.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant regardless of nucleotide change'. The evidence for this variant shows: no known pathogenic variant at residue T1771 with the same amino acid change. Therefore, this criterion is not applied because no matching pathogenic amino acid change has been reported.
PS2 (Not Applied)
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 status has been determined due to lack of parental testing. Therefore, this criterion is not applied because de novo occurrence has not been demonstrated.
PS3 (Not Applied)
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 assays have been performed. Therefore, this criterion is not applied because functional data are absent.
PS4 (Not Applied)
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 affected cohort data demonstrating enrichment. Therefore, this criterion is not applied because no statistical evidence of increased prevalence in affected individuals is available.
PM1 (Not Applied)
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: T1771 is outside the known exonuclease domain hotspot (residues ~268–471) and no evidence of a functional domain at this position. Therefore, this criterion is not applied because the variant does not lie within a defined mutational hotspot or critical domain.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive) in population databases'. The evidence for this variant shows: present in gnomAD at MAF 0.00399%, which is below thresholds for common variants. Therefore, this criterion is applied at Moderate strength because the variant is absent or extremely rare in population databases.
PM3 (Not Applied)
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 trans phase with a pathogenic variant and POLE-associated disease is dominantly inherited. Therefore, this criterion is not applied because the variant is not evaluated in a recessive context.
PM4 (Not Applied)
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 and does not alter protein length. Therefore, this criterion is not applied because no length change occurs.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different missense change has been seen as pathogenic'. The evidence for this variant shows: no pathogenic missense variants reported at residue T1771. Therefore, this criterion is not applied because no other pathogenic change is known at this residue.
PM6 (Not Applied)
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 parental testing or de novo assumption data. Therefore, this criterion is not applied because de novo status without confirmation has not been established.
PP1 (Not Applied)
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 studies. Therefore, this criterion is not applied because segregation data are lacking.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: POLE disease is associated with missense variants in the exonuclease domain, but T1771M lies outside that region. Therefore, this criterion is not applied because the variant is not in a region known for disease-causing missense and benign missense variation rate context is unclear.
PP3 (Not Applied)
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 or tolerated effect. Therefore, this criterion is not applied because in silico predictions do not support a deleterious impact.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied because phenotype specificity has not been assessed.
PP5 (Not Applied)
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 submissions report Uncertain Significance, not pathogenic. Therefore, this criterion is not applied because no authoritative source reports pathogenicity.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is greater than 5% in population databases'. The evidence for this variant shows: MAF 0.00399% in gnomAD. Therefore, this criterion is not applied because allele frequency is well below 5%.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for disorder'. The evidence for this variant shows: MAF 0.00399% does not exceed expected frequency for POLE-related disease. Therefore, this criterion is not applied because population frequency is not higher than expected.
BS2 (Not Applied)
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: variant present in gnomAD, but data on clinical status and age are not available. Therefore, this criterion is not applied because unaffected status of carriers is not confirmed.
BS3 (Not Applied)
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 because functional evidence is absent.
BS4 (Not Applied)
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 in affected families. Therefore, this criterion is not applied because segregation has not been assessed.
BP1 (Not Applied)
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: POLE disease mechanism involves missense variants in the exonuclease domain rather than pure loss of function. Therefore, this criterion is not applied because missense variants can be disease-causing.
BP2 (Not Applied)
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 phase data with other variants. Therefore, this criterion is not applied because phasing information with known pathogenic variants is lacking.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without a known function'. The evidence for this variant shows: it is a single nucleotide change resulting in a missense, not an indel. Therefore, this criterion is not applied because it does not involve an in-frame indel.
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: in silico tools including CADD score 3.82, PolyPhen-2, MetaSVM, and MetaLR predict benign or tolerated effect, and SpliceAI maximum score 0.04 indicating negligible splicing impact. Therefore, this criterion is applied at Supporting strength because multiple computational predictions indicate a benign effect.
BP5 (Not Applied)
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 reports of this variant occurring in a case with a different known molecular cause. Therefore, this criterion is not applied because there is no evidence of an alternate molecular basis.
BP6 (Not Applied)
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 reports Uncertain Significance, not benign. Therefore, this criterion is not applied because no source reports benign classification.
BP7 (Not Applied)
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 variant. Therefore, this criterion is not applied because the variant is not synonymous.