ClinVar Genomic variation as it relates to human health

APC NM_000038.5 exon 15 p.Ala1050Glufs*6 (c.3149del): This variant has been reported in the literature in several individuals with familial adenomatous polyposis (FAP) (Freidl 2001 PMID:11247895, Friedl 2005 PMID:20223039, Cruz-Correa 2013 PMID:23460355, Inra 2015 PMID:25590978). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:183078). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 6 amino acids downstream from this location. This variant occurs within the last exon of the gene and therefore may escape nonsense medicated decay. However, this variant still leads to a loss >50% of the protein. Additionally, several other truncating variants downstream of this one have been reported in ClinVar as pathogenic. Of note, this variant affects the carboxyl-terminal of the protein, which is thought to be important for microtubule interaction and EB1 protein binding (Wen 2004 PMID:15311282, Moseley 2007 PMID:17293347). In summary, this variant is classified as pathogenic based on the data above.

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

Variant summary: APC c.3149delC (p.Ala1050GlufsX6) results in a premature termination codon, and although it is not expected to undergo nonsense mediated decay, it is predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250600 control chromosomes (gnomAD). c.3149delC has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (FAP), including those who also have a positive family history of FAP and/or colorectal cancer (e.g. Friedl_2001, Cruz-Correa_2013, Inra_2015). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23460355, 11247896, 20223039, 25590978). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Ala1050Glufs*6) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1794 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: 11247896, 23460355, 25590978). ClinVar contains an entry for this variant (Variation ID: 183078). 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.

proposed classification - variant undergoing re-assessment, contact laboratory

The c.3149delC pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 3149, causing a translational frameshift with a predicted alternate stop codon (p.A1050Efs*6). This mutation hsa been detected in multiple individuals with Familial Adenomatous Polyposis (FAP) (Friedl W et al. Gut. 2001 Apr;48:515-21; Friedl W and Aretz S. Hered Cancer Clin Pract. 2005 Sep;3:95-114; Steinhagen E et al. Clin Colorectal Cancer. 2012 Dec;11:304-8; Cruz-Correa M et al. Fam. Cancer. 2013 Sep;12:555-62; Inra JA et al. Genet. Med. 2015 Oct;17:815-21; Casellas-Cabrera N et al. Fam. Cancer. 2016 Apr;15:267-74). 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.

The APC c.3149delC variant is predicted to result in a frameshift and premature protein termination (p.Ala1050Glufs*6). This variant has been reported in individuals and/or families with adenomatous polyposis coli and/or colorectal cancer (Table 2, Friedl et al. 2001. PubMed ID: 11247896; Table S1, Friedl et al. 2005. PubMed ID: 20223039; Table 2, Cruz-Correa et al. 2013. PubMed ID: 23460355; Table S5, Inra et al. 2015. PubMed ID: 25590978). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/183078/). This variant resides within the final exon of this gene and it is unclear if the resulting mRNA would undergo nonsense mediated decay: However, downstream truncating variants of this variant are reported to be pathogenic (e.g. Brensinger et al. 1998. PubMed ID: 9824584). Frameshift variants in APC are expected to be pathogenic. This variant is interpreted as pathogenic.