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
POLE
Final classification
VUS
POLE c.5312C>T · p.Thr1771Met
POLE
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
Gene diagram
· NM_006231.4 · variants mapped to exon structure
POLE
NM_006231.4
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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