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.
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.
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.
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.
