POLE c.4856A>G, p.Tyr1619Cys
NM_006231.4:c.4856A>G
Variant of Uncertain Significance (VUS)
NM_006231.4:c.4856A>G (Y1619C) in POLE is classified as a Variant of Uncertain Significance. It meets PM2 (Moderate) due to absence from population databases and BP4 (Supporting) based on predominantly benign computational predictions. No additional evidence is available to support a definitive pathogenic or benign 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.4856A>G
Protein Change
Y1619C
Location
Exon 37
(Exon 37 of 49)
5'Exon Structure (49 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1619 in gene POLE
Variant interpretation based on transcript NM_006231.4
Genome Browser
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HGVS InputNM_006231:c.4856A>G
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
Uncertain Significance (VUS)
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (3 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 1619 in gene POLE
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.689
0.689
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:
polyphen_prediction: probably_damaging
Benign:
CADD: 4.85metasvm: Tmetalr: Tprimateai: 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: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: NM_006231.4:c.4856A>G is a missense change (Y1619C), not a null variant. Therefore, this criterion is not applied because the variant does not create a predicted loss-of-function allele.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS1 is: "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 causing the Y1619C amino acid change. Therefore, this criterion is not applied because there is no match to a known pathogenic amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 information on de novo status or parental testing. Therefore, this criterion is not applied because de novo occurrence has not been demonstrated.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 for POLE Y1619C. Therefore, this criterion is not applied because functional evidence is lacking.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 because there is no evidence of increased prevalence in affected individuals.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: no specific data indicating that Y1619 is in a mutational hotspot or known functional 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: "Absent from controls (or at extremely low frequency if recessive) (Table 6) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium". The evidence for this variant shows: NM_006231.4:c.4856A>G is not present in population databases including gnomAD (MAF = 0%). Therefore, this criterion is applied at Moderate strength because the variant is absent from large population cohorts.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no evidence of occurrence in trans with another pathogenic POLE variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: Y1619C is a missense substitution without change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 alterations reported at residue Y1619. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo or parental origin data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family 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: "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 overall missense constraint for POLE and mixed variant mechanism. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product (e.g., conservation, splicing impact)". The evidence for this variant shows: in silico predictions are mixed (PolyPhen probably damaging vs. other tools benign) and SpliceAI predicts no splicing impact. Therefore, this criterion is not applied due to conflicting computational results.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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 detailed phenotype or disease-specific family history provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: ClinVar entries report VUS, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: allele frequency is 0% in population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: allele frequency is absent in controls. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS2 is: "Observed in a healthy adult individual for a dominant (with full penetrance expected at an early age), X-linked or mitochondrial disorder with full penetrance expected at an early age". The evidence for this variant shows: no reports of the variant in healthy adults. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding 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.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation analysis performed. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: POLE disease mechanism includes missense variants affecting polymerase proofreading, 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: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no evidence of cis/trans occurrence with another variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: Y1619C is a missense change, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule/finding for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)". The evidence for this variant shows: SpliceAI predicts no splicing impact, and although PolyPhen is probably damaging, multiple other tools (CADD, MetaSVM, MetaLR, PrimateAI, FATHMM) predict benign. Therefore, this criterion is applied at Supporting strength because the majority of in silico data do not support a functional impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such case reports. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: no reputable source reports this variant as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: NM_006231.4:c.4856A>G is a missense variant, not synonymous. Therefore, this criterion is not applied.