ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6670A>G (p.Ile2224Val) (rs374597207)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159566 SCV000209538 uncertain significance not provided 2017-12-27 criteria provided, single submitter clinical testing This variant is denoted APC c.6670A>G at the cDNA level, p.Ile2224Val (I2224V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). This variant was observed in at least one individual that underwent hereditary cancer panel testing (Yorczyk 2015). APC Ile2224Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the basic 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 Ile2224Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575448 SCV000667659 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000575448 SCV000687089 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing
Invitae RCV000646418 SCV000768188 uncertain significance Familial adenomatous polyposis 1 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2224 of the APC protein (p.Ile2224Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs374597207, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 181814). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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