ClinVar Genomic variation as it relates to human health

Variant summary: The c.2161_2170delGGAAGTGCTG (p.Gly721Glnfs) variant in APC gene is a frameshift change that results in the loss of the ~2123 amino acids of APC protein (~75%). This change is predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The variant is absent from the large control population datasets of ExAC and gnomAD (120756 and 245146 chrs tested, respectively). The c.2161_2170delGGAAGTGCTG has not, to our knowledge, been reported in affected individuals via published reports or cited by reputable databases/clinical laboratories. Other overlapping truncated variants, such as c.2162delG and c.2169delT, have been reported in association with APC. Based on the location of this variant within exon 16, it is expected to result in classical FAP. Taken together, the variant was classified as Pathogenic.

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the APC protein in which other variant(s) (p.Tyr2645Lysfs*14) have been determined to be pathogenic (PMID: 1316610, 8381579, 9824584, 22135120, 27081525; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 495355). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly721Glnfs*3) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2123 amino acid(s) of the APC protein.