ClinVar Genomic variation as it relates to human health

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.

Variant summary: POLD1 c.2862G>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0036 in 179660 control chromosomes, predominantly within the African subpopulation at a frequency of 0.036 in the gnomAD database, including 8 homozygotes. The observed variant frequency within African control individuals is approximately 2534 fold above the estimated maximal expected allele frequency for a pathogenic variant in POLD1 causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. Although POLD1 pseudogenes may complicate NGS mapping, our analysis shows that the variant of interest lies within a region that is not homologous to any other region of the genome, suggesting the variant is real and localized to the POLD1 gene. To our knowledge, no occurrence of c.2862G>C in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

The POLD1 p.Thr954Thr variant was not identified in the literature nor was it identified in the Cosmic and MutDB databases. The variant was identified in dbSNP (ID: rs3219440) “With Likely benign allele”,bClinVar (classified benign by Invitae, Counsyl, Ambry Genetics, Quest Diagnostics Nichols Institute San Juan Capistrano; and likely benign GeneDx), Clinvitae (2x), and in control databases in 651 (8 homozygous) of 179660 chromosomes at a frequency of 0.004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 587 (8 homozygous) of 16318 chromosomes (freq: 0.04), Other in 5 of 4808 chromosomes (freq: 0.001), Latino in 52 of 24830 chromosomes (freq: 0.002), European Non-Finnish in 6 of 71940 chromosomes (freq: 0.00008), and South Asian in 1 of 22912 chromosomes (freq: 0.00004), while not observed in the Ashkenazi Jewish, East Asian and European Finnish populations. The p.Thr954= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.