ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5752A>G (p.Ile1918Val) (rs776966222)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204791 SCV000259784 uncertain significance Familial adenomatous polyposis 1 2018-11-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1918 of the APC protein (p.Ile1918Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs776966222, ExAC 0.01%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 219739). 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.
Counsyl RCV000204791 SCV000489262 uncertain significance Familial adenomatous polyposis 1 2016-09-16 criteria provided, single submitter clinical testing
GeneDx RCV000481360 SCV000570889 uncertain significance not provided 2018-02-27 criteria provided, single submitter clinical testing This variant is denoted APC c.5752A>G at the cDNA level, p.Ile1918Val (I1918V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has been observed in at least one individual with colorectal cancer (Yurgelun 2017). APC Ile1918Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the 20-aa repeat B-catenin down-regulating domain and the SAMP repeats/axin binding 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 Ile1918Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574367 SCV000667361 likely benign Hereditary cancer-predisposing syndrome 2016-11-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000574367 SCV000687042 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-26 criteria provided, single submitter clinical testing

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