ClinVar Genomic variation as it relates to human health

Variant summary: The POLE c.5678+4C>T variant involves the alteration of a non-conserved nucleotide located in an intronic position outside of the canonical slice sites. Mutation taster predicts a benign outcome for this variant along with 4/5 in silico splice site tools predicting the variant not to have an impact on splicing. This variant was found in 550/121298 control chromosomes (16 homozygotes), predominantly observed in the African, 16 homozygotes subpopulation at a frequency of 0.0479531 (499/10406). This frequency is about 3376 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of African. In addition a clinical diagnostic laboratory classified this variant as Benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as Benign.

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

The POLE c.5678+4C>T variant was not identified in the literature. The variant was identified in dbSNP (ID: rs5744973) as "With Benign allele" and ClinVar (classified as benign by Invitae, Counsyl, GeneDx, Ambry Genetics, and four other clinical laboratories). The variant was identified in control databases in 1227 of 276680 chromosomes (23 homozygous) at a frequency of 0.004, 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 1091 of 24018 chromosomes (freq: 0.045), Other in 17 of 6462 chromosomes (freq: 0.003), Latino in 77 of 34402 chromosomes (freq: 0.002), European in 40 of 126262 chromosomes (freq: 0.0003), and South Asian in 2 of 30770 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The c.5678+4C>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 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, this variant meets our laboratory's criteria to be classified as benign.