Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000478497 | SCV000569397 | uncertain significance | not provided | 2016-02-16 | criteria provided, single submitter | clinical testing | This deletion of 2 nucleotides in POLD1 is denoted c.2309_2310delAG at the cDNA level and p.Glu770GlyfsX25 (E770GfsX25) at the protein level. The normal sequence, with the bases that are deleted in braces, is GCTG[AG]GCGA. The deletion causes a frameshift which changes a Glutamic Acid to a Glycine at codon 770, and creates a premature stop codon at position 25 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has not, to our knowledge, been published in the literature. While some missense variants have been recognized as an underlying cause of Polymerase Proofreading-Associated Polyposis (PPAP), there are no data at this time to support that loss-of-function variants confer the same cancer risks. We therefore consider POLD1 c.2309_2310delAG to be a variant of unknown significance with respect to cancer. |
Invitae | RCV000801743 | SCV000941536 | uncertain significance | Colorectal cancer, susceptibility to, 10 | 2018-10-02 | criteria provided, single submitter | clinical testing | Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLE protein, while not abolishing its polymerase enzyme activity, are associated with an increased risk for colonic adenomatous polyps and colon cancer (PMID: 23263490, 23447401). Loss-of-function truncating variants, which result in an absent or severely disrupted POLE protein, are therefore unlikely to be associated with disease. Without further clinical and genetic evidence, however, this variant has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals with POLD1-related disease. ClinVar contains an entry for this variant (Variation ID: 420528). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu770Glyfs*25) in the POLD1 gene. It is expected to result in an absent or disrupted protein product. |