ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3073A>G (p.Ile1025Val) (rs370591349)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159546 SCV000209510 uncertain significance not provided 2014-10-01 criteria provided, single submitter clinical testing This variant is denoted APC c.3073A>G at the cDNA level, p.Ile1025Val (I1025V) 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 pathogenic or benign. APC Ile1025Val was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Ile1025Val occurs at a position that is conserved across species and is located in a domain responsible for down-regulation through a process mediated by direct ubiquitination (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Ile1025Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000218802 SCV000275523 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000551625 SCV000647420 uncertain significance Familial adenomatous polyposis 1 2018-08-17 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1025 of the APC protein (p.Ile1025Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs370591349, ExAC 0.002%) but has not been reported in the literature in individuals with an APC-related disease. ClinVar contains an entry for this variant (Variation ID: 181798). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function and RNA splicing. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000218802 SCV000905974 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-15 criteria provided, single submitter clinical testing

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