ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4669A>G (p.Ile1557Val) (rs763578917)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589170 SCV000292773 uncertain significance not provided 2018-11-23 criteria provided, single submitter clinical testing This variant is denoted APC c.4669A>G at the cDNA level, p.Ile1557Val (I1557V) 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 Ile1557Val was observed at an allele frequency of 0.02% (19/125688) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the beta-catenin down-regulating domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Ile1557Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000469610 SCV000552671 uncertain significance Familial adenomatous polyposis 1 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1557 of the APC protein (p.Ile1557Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs763578917, ExAC 0.02%), 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: 245712). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000491300 SCV000579816 likely benign Hereditary cancer-predisposing syndrome 2018-02-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Other strong data supporting benign classification
Integrated Genetics/Laboratory Corporation of America RCV000589170 SCV000694056 likely benign not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The APC c.4669A>G (p.Ile1557Val) variant involves the alteration of a non-conserved nucleotide, which is not located in any known domain (InterPro). 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 14/120490 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0001962 (13/66264). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.
Color RCV000491300 SCV000910831 likely benign Hereditary cancer-predisposing syndrome 2017-01-04 criteria provided, single submitter clinical testing

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