ClinVar

Description

The POLE p.Lys1857Arg variant was not identified in the literature nor was it identified in the Cosmic database. The variant was identified in dbSNP (ID: rs5744971) as "With Uncertain significance, other allele ", ClinVar (classified as benign by Invitae and one clinical laboratory; as likely benign by GeneDx, Ambry Genetics and two clinical laboratories), and in MutDB, databases. The variant was identified in control databases in 256 of 277088 chromosomes at a frequency of 0.0009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 238 of 24034 chromosomes (freq: 0.01), Other in 2 of 6462 chromosomes (freq: 0.0003), Latino in 15 of 34396 chromosomes (freq: 0.0004), European in 1 of 126646 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Lys1857 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.