ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6127A>G (p.Ile2043Val) (rs876660233)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217035 SCV000277480 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000456656 SCV000552635 uncertain significance Familial adenomatous polyposis 1 2018-06-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2043 of the APC protein (p.Ile2043Val). The isoleucine residue is highly 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 an APC-related disease. ClinVar contains an entry for this variant (Variation ID: 233160). 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, this variant has uncertain impact on APC function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000217035 SCV000904771 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780836 SCV000918436 uncertain significance not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: APC c.6127A>G (p.Ile2043Val) results in a conservative amino acid change located in the SAMP domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-06 in 276604 control chromosomes. This frequency is not higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (7.2e-06 vs 7.1e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.6127A>G in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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