ClinVar Miner

Submissions for variant NM_000038.6(APC):c.8212A>G (p.Ile2738Val) (rs876658839)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221398 SCV000274605 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
Illumina Clinical Services Laboratory,Illumina RCV000379852 SCV000452056 uncertain significance APC-Associated Polyposis Disorders 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000461552 SCV000552487 uncertain significance Familial adenomatous polyposis 1 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2738 of the APC protein (p.Ile2738Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 230912). 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. 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.
GeneDx RCV000487304 SCV000567885 uncertain significance not provided 2018-12-14 criteria provided, single submitter clinical testing This variant is denoted APC c.8212A>G at the cDNA level, p.Ile2738Val (I2738V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. APC Ile2738Val was not observed in large population cohorts (Lek 2016). This variant is located in the EB1 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 Ile2738Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000221398 SCV000681915 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-09 criteria provided, single submitter clinical testing

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