ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6403A>G (p.Ile2135Val) (rs757633174)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480863 SCV000564580 uncertain significance not provided 2018-03-22 criteria provided, single submitter clinical testing This variant is denoted APC c.6403A>G at the cDNA level, p.Ile2135Val (I2135V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ile2135Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Ile2135Val 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 evidence, it is unclear whether APC Ile2135Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000532793 SCV000647642 uncertain significance Familial adenomatous polyposis 1 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2135 of the APC protein (p.Ile2135Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs757633174, ExAC 0.003%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 418014). 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.
Ambry Genetics RCV000566531 SCV000672529 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000566531 SCV000904172 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing

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