ClinVar Genomic variation as it relates to human health

Variant summary: APC c.3184_3187delCAAA (p.Gln1062ValfsX63) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250490 control chromosomes (gnomAD). c.3184_3187delCAAA has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (e.g. Miyaki_1994, vanderLuijt_1997, Plawski_2008). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

This sequence change creates a premature translational stop signal (p.Gln1062Valfs*63) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1782 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 8730280, 20223039, 20685668). ClinVar contains an entry for this variant (Variation ID: 428100). 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. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

The c.3184_3187delCAAA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 3184 to 3187, causing a translational frameshift with a predicted alternate stop codon (p.Q1062Vfs*63). This mutation has been detected in multiple individuals and families diagnosed with familial adenomatous polyposis (FAP) (Mandl M et al. Hum. Mol. Genet., 1994 Jan;3:181-4; Dobbie Z et al. J. Med. Genet., 1996 Apr;33:274-80; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Plawski A et al. J. Appl. Genet., 2008;49:407-14). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.