The POLE c.5312C>T (p.Thr1771Met) variant has been observed in somatic cancers in COSMIC (COSV57679989, n=2) and has been reported in ClinVar as a variant of uncertain significance.1 The variant is present at low frequency in population databases, with gnomAD v2.1 AF 3.9888e-05 (10/250702) and gnomAD v4.1 AF 4.09054e-05 (66/1613480), with no homozygotes reported; these values are below the PM2 threshold of 0.1% and below the BS1 and BA1 thresholds of 0.3% and 1%, respectively.2 No validated variant-specific functional assay evidence was identified for p.(Thr1771Met).3 SpliceAI predicts no significant splice impact (maximum delta score 0.04), and the local REVEL score is 0.178; however, the variant is not represented in the León-Castillo POLE supplementary computational tables, so the custom POLE PP3 and BP4 rules were not applied.4
Final classification
VUS
PM2
POLE
c.5312C>T
p.Thr1771Met
This variant
The POLE c.5312C>T (p.Thr1771Met) variant has been observed in somatic cancers in COSMIC (COSV57679989, n=2) and has been reported in ClinVar as a variant of uncertain significance.
The León-Castillo et al. 2020 custom POLE framework was used as the applicable final-classification framework; it customizes selected POLE criterion specifications while retaining standard ACMG/AMP 2015 final combination thresholds.
Classification rationale
PM2
VUS
POLE c.5312C>T
PM2
→
VUS
3
oncokb ↗
4
spliceai ↗vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_3vcep_p_a_t_h___2_5_0___3_2_3___s_0_0_4
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_006231.4 · variants mapped to exon structure
POLE
NM_006231.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 20 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
PM2
Moderate
review
Pathogenic
This variant is present at low frequency in population databases, with gnomAD v2.1 AF 3.9888e-05 (0.00399%, 10/250702 alleles) and gnomAD v4.1 AF 4.09054e-05 (0.00409%, 66/1613480 alleles), both below the project's PM2 threshold of 0.1%, with no homozygotes reported.
gnomAD v2.1 AF 3.9888e-05; 10/250702 alleles; homozygotes = 0.gnomAD v4.1 AF 4.09054e-05; 66/1613480 alleles; homozygotes = 0.
Assessed · not applied
· 4 not met · 16 not assessed
Pathogenic
PS1
No evidence was identified showing that a different nucleotide change causing the same amino acid substitution p.(Thr1771Met) is established as pathogenic or likely pathogenic.
PS2
No confirmed de novo occurrence with parental confirmation was identified.
PS3
No validated variant-specific functional studies were identified showing a damaging effect for p.(Thr1771Met).
PS4
Under the custom POLE framework, PS4 is restricted to exact variants recurrent in both COSMIC and TCGA endometrial carcinoma cohorts with combined count at least 10 and belonging to the established pathogenic set.
PM1
The custom POLE framework does not assign PM1 by domain location alone and limits PM1 to specific exact substitutions from León-Castillo et al.
PM5
No evidence was identified for a different pathogenic or likely pathogenic missense change affecting the same amino acid residue Thr1771.
PM6
No assumed de novo occurrence data were identified.
PP1
No segregation data were identified to show co-segregation with disease in affected relatives.
PP2
No gene-level evidence was retrieved showing that POLE has a low rate of benign missense variation together with missense variants as a common disease mechanism in a way that would support PP2 for this review.
PP3
The custom POLE PP3 rule requires the exact variant to appear in León-Castillo Supplementary Table S2 or S3 with a REVEL class of 'likely disease causing' and no more than 1 benign in silico result.
PP4
No phenotype-specific clinical presentation or tumor signature evidence was identified that would support a highly specific POLE-associated presentation for this variant.
Benign
BA1
Population frequency is below the benign stand-alone threshold: gnomAD v2.1 AF is 0.00399% and gnomAD v4.1 AF is 0.00409%, both well below the BA1 threshold of 1%.
BS1
Population frequency is below the strong benign threshold: gnomAD v2.1 AF is 0.00399% and gnomAD v4.1 AF is 0.00409%, both below the BS1 threshold of 0.3%.
BS2
No evidence was identified showing this variant in a sufficient number of well-characterized unaffected individuals for BS2.
BS3
No validated variant-specific functional studies were identified showing no damaging effect for p.(Thr1771Met).
BS4
No nonsegregation data were identified.
BP1
No gene-specific framework was retrieved supporting BP1 for missense variation in POLE.
BP2
No phase or co-occurrence data were identified to support BP2.
BP4
The custom POLE BP4 rule requires the exact variant to appear in León-Castillo Supplementary Table S2 or S3 with REVEL class 'Likely benign' or 'Likely-benign' and at least 4 benign in silico results.
BP5
No alternate molecular diagnosis or other variant explaining the phenotype was identified.
N/A · 7
PVS1 · PM3 · PM4 · PP5 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.09054e-05; MAF= 0.00409%, 66/1613480 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.00016442; MAF= 0.01644%, 1/6082 alleles, homozygotes = 0); grpmax FAF= 4.019e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.9888e-05; MAF= 0.00399%, 10/250702 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163132; MAF= 0.01631%, 1/6130 alleles, homozygotes = 0); grpmax FAF= 2.856e-05.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0041%
· 66 / 1,613,480
0 hom · FAF 0.004%
0 hom · FAF 0.004%
Middle Eastern 1 / 6,082 |
0.016% |
European (non-Finnish) 60 / 1,180,026 |
0.0051% |
Remaining individuals 2 / 62,482 |
0.0032% |
African/African American 2 / 74,932 |
0.0027% |
Admixed American 1 / 60,004 |
0.0017% |
+ 5 not observed (European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.004%
· 10 / 250,702
0 hom · FAF 0.0029%
0 hom · FAF 0.0029%
Remaining individuals 1 / 6,130 |
0.016% |
European (non-Finnish) 7 / 113,630 |
0.0062% |
East Asian 1 / 18,390 |
0.0054% |
Admixed American 1 / 34,584 |
0.0029% |
+ 4 not observed (African/African American, Ashkenazi Jewish, European (Finnish), South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
Functional
Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: POLE, the catalytic subunit of DNA polymerase epsilon, is an enzyme involved in DNA replication and repair. Select POLE mutations lead to ultra-high m
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57679989, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links