POLE c.1331T>A, p.Met444Lys
NM_006231.4:c.1331T>A
COSMIC ID: COSM937323
Likely Pathogenic
The POLE c.1331T>A (p.M444K) variant has strong functional evidence of damaging effect (PS3), is absent from population databases (PM2), lies within the exonuclease functional domain (PM1), and shows overall benign computational predictions (BP4). The combination of one Strong, two Moderate, and one Supporting criterion supports a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PS3
PM1
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.1331T>A
Protein Change
M444K
Location
Exon 13
(Exon 13 of 49)
5'Exon Structure (49 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 444 in gene POLE
Alternate Identifiers
COSM937323
Variant interpretation based on transcript NM_006231.4
Genome Browser
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HGVS InputNM_006231:c.1331T>A
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
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 444 in gene POLE
Functional Summary
The POLE M444K variant has been functionally characterized and is likely to have a damaging effect. It is located in the exonuclease domain of the POLE protein and is recurrent in ultramutated endometrial carcinoma. Functional analysis using a POLE-score, which evaluates tumor mutation burden and mutation signature, suggests that this variant is likely inactivating.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.621
0.621
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_damagingmetasvm: D
Benign:
CADD: 4.34metalr: 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 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: it is a missense change (M444K), not a null variant. Therefore, this criterion is not applied at any strength because the variant type does not meet PVS1.
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: no other nucleotide change resulting in M444K has been reported as pathogenic. Therefore, this criterion is not applied because the variant does not match a known pathogenic nucleotide 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 status or parentage confirmation data available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Strong)
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: functional characterization demonstrates damaging effect in the POLE exonuclease domain with recurrent ultramutated endometrial carcinoma signature and POLE-score indicating inactivation. Therefore, this criterion is applied at Strong strength because well-established in vitro/in vivo studies support a damaging effect.
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 or cohort prevalence data available. Therefore, this criterion is not applied due to lack of prevalence statistics.
PM1
PM1 (Moderate)
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: M444K lies within the exonuclease domain of POLE, a known functional domain critical for proofreading, with no benign variation reported in this region. Therefore, this criterion is applied at Moderate strength because the variant resides in a well‐established functional domain.
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: absent from gnomAD, 1000 Genomes, ESP, and ExAC databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from population controls.
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 trans configuration with another pathogenic allele. Therefore, this criterion is not applied due to lack of trans detection data.
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 missense substitution without alteration of protein length. Therefore, this criterion is not applied because there is no length change.
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: no other pathogenic missense variants reported at residue M444. Therefore, this criterion is not applied because the residue has no reported pathogenic missense changes.
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 or parental confirmation information. Therefore, this criterion is not applied due to absence of de novo assumption data.
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 familial segregation data available. Therefore, this criterion is not applied due to lack of segregation information.
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: insufficient data on overall missense constraint or rate of benign missense in POLE. Therefore, this criterion is not applied due to lack of specific missense constraint metrics.
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 (e.g., conservation, splicing impact)". The evidence for this variant shows: mixed in silico predictions with both damaging and benign outputs; SpliceAI score 0.02 indicating no splicing impact. Therefore, this criterion is not applied because computational evidence is conflicting.
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 phenotype or clinical presentation details provided. Therefore, this criterion is not applied due to absence of phenotype data.
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: not found in ClinVar or other curated databases. Therefore, this criterion is not applied because no reputable source report exists.
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: allele frequency is 0% in population databases. Therefore, this criterion is not applied because the frequency is not too 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: allele frequency is absent/very low. Therefore, this criterion is not applied because the frequency does not exceed expected thresholds.
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 observations in healthy individuals documented. Therefore, this criterion is not applied due to absence of healthy cohort data.
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: functional studies indicate damaging effect. Therefore, this criterion is not applied because functional data support pathogenicity, not benign effect.
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 studies available. Therefore, this criterion is not applied due to lack of segregation data.
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: POLE disease mechanism involves missense defects in exonuclease domain. Therefore, this criterion is not applied because missense is a known mechanism.
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 phase data with other variants. Therefore, this criterion is not applied due to lack of phasing information.
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 missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact". The evidence for this variant shows: mixed in silico predictions with benign majority from CADD (4.34), MetaLR, PrimateAI, and SpliceAI score 0.02 indicating no splicing impact. Therefore, this criterion is applied at Supporting strength because computational data lean benign overall.
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 alternate molecular diagnoses reported in cases. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
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: not reported as benign in any source. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
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, not synonymous. Therefore, this criterion is not applied.