The POLE c.1718G>A (p.Arg573Gln) variant has not been observed in COSMIC somatic cancer records and has been reported in ClinVar as uncertain significance by 3 clinical laboratories.1 This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at a very low overall allele frequency of 1.85855e-06 (0.00019%, 3/1614158 alleles), with the highest observed population frequency 0.000165017 (0.01650%, 1/6060 alleles), which remains below the 0.1% PM2 rarity threshold.2 p.Arg573Gln is not listed among the recurrent POLE exonuclease-domain variants in León-Castillo et al. Supplementary Table S1 and was not identified in the Cancer Hotspots review, which does not support PM1 or the POLE-specific PS4 recurrence rule.3 Available computational evidence does not support a protein-damaging or benign in silico assignment because this exact variant is not listed in the POLE supplementary in silico tables, REVEL is 0.228, and SpliceAI shows a possible splice impact with a max delta score of 0.20.4
POLE
Final classification
VUS
POLE c.1718G>A · p.Arg573Gln
POLE
The POLE c.1718G>A (p.Arg573Gln) variant has not been observed in COSMIC somatic cancer records and has been reported in ClinVar as uncertain significance by 3 clinical laboratories.
León-Castillo et al. 2020 custom POLE framework for criterion specification, using ACMG/AMP 2015 final classification combination thresholds as defined in the explicit final-classification framework.
Classification rationale
PM2
VUS
POLE c.1718G>A
PM2
→
VUS
1
output/evidence.json:results.cosmicoutput/case_summary.json:compact_evidence.clinvar
2
output/evidence.json:results.gnomad.GNOMAD_V2_1output/evidence.json:results.gnomad.GNOMAD_V4_1
3
vcep_db/POLE/files/PATH-250-323-s002.xlsxoutput/evidence.json:results.hotspotsoutput/final_classification_framework.json
4
vcep_db/POLE/files/PATH-250-323-s003.xlsxvcep_db/POLE/files/PATH-250-323-s004.xlsxoutput/evidence.json:results.reveloutput/evidence.json:results.spliceai
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= 1.85855e-06; MAF= 0.00019%, 3/1614158 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165017; MAF= 0.01650%, 1/6060 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,614,158
0 hom
0 hom
Middle Eastern 1 / 6,060 |
0.017% |
Admixed American 1 / 60,010 |
0.0017% |
Remaining individuals 1 / 62,512 |
0.0016% |
+ 7 not observed (European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.20).
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links