ClinVar Genomic variation as it relates to human health

This variant inserts 1 nucleotide in exon 16 of the APC gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Variant summary: APC c.4970dupT (p.Ser1658LysfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein, including the basic domain (IPR009234) and the EB-1 binding domain (IPR009232). At least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant was absent in 250680 control chromosomes (gnomAD). c.4970dupT has been reported in the literature in an individual undergoing multigene panel testing for genes involved in DNA mismatch repair and/or Familial Adenomatous Polyposis (Rey_2017). This report does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have 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 likely 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.Ser1658Lysfs*2) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1186 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 487050). 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.4970dupT pathogenic mutation, located in coding exon 15 of the APC gene, results from a duplication of T at nucleotide position 4970, causing a translational frameshift with a predicted alternate stop codon (p.S1658Kfs*2). This alteration occurs at the 3' terminus of the APC gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 44% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.