ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3529A>G (p.Ile1177Val) (rs369834416)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000473845 SCV000552457 uncertain significance Familial adenomatous polyposis 1 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1177 of the APC protein (p.Ile1177Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs369834416, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 411342). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000481597 SCV000564569 uncertain significance not provided 2018-11-16 criteria provided, single submitter clinical testing This variant is denoted APC c.3529A>G at the cDNA level, p.Ile1177Val (I1177V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. APC Ile1177Val was observed at an allele frequency of 0.026% (8/30,778) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether APC Ile1177Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570317 SCV000667400 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000570317 SCV000681611 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779718 SCV000916478 uncertain significance not specified 2018-08-31 criteria provided, single submitter clinical testing Variant summary: APC c.3529A>G (p.Ile1177Val) results in a conservative amino acid change located in the Adenomatous polyposis coli protein, 15 residue repeat of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 245696 control chromosomes. The observed variant frequency is approximately 1.2-fold above the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), suggesting that the variant may be benign. c.3529A>G has been reported in the literature in individuals affected with cancer. This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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