ClinVar Genomic variation as it relates to human health

Variant summary: APC c.3329C>G (p.Ser1110X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250468 control chromosomes. c.3329C>G has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (Nagase_1992, Miyaki_1994, Renkonen_2005, Andresen_2009). 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

The APC p.Ser1110* variant was identified in 4 of 1966 proband chromosomes (frequency: 0.002) from individuals or families with FAP (Enomoto 2000, Lagarde 2010, Miyaki 1994). The variant was also identified in LOVD 3.0 (2X ). The variant was not identified in dbSNP or ClinVar. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3329C>G variant leads to a premature stop codon at position 1110 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in APC associated cancers and is the type of variant expected to cause the disorder. In addition, the study on the relationship between germline mutation of the APC gene and extra-colonic manifestations suggests that mutant APC proteins truncated after codon 1110 may have significant dominant negative effects on the wild-type APC protein, compared with mutant APC proteins truncated before codon 1110 (Enomoto 2000). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.