ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2297C>T (p.Ala766Val) (rs200339830)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199077 SCV000253998 uncertain significance Familial adenomatous polyposis 1 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 766 of the APC protein (p.Ala766Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs200339830, ExAC 0.01%). This variant has not been reported in the literature in individuals with a APC-related disease. ClinVar contains an entry for this variant (Variation ID: 41522). 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: "Deleterious"; 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.
GeneDx RCV000034407 SCV000292451 uncertain significance not provided 2017-10-23 criteria provided, single submitter clinical testing This variant is denoted APC c.2297C>T at the cDNA level, p.Ala766Val (A766V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). This variant was observed in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). APC Ala766Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Ala766Val occurs at a position that is conserved across species and is located in the Armadillo Region (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Ala766Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000199077 SCV000489345 uncertain significance Familial adenomatous polyposis 1 2016-09-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562498 SCV000667287 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000562498 SCV000681515 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034407 SCV000805379 uncertain significance not provided 2018-01-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779709 SCV000916464 uncertain significance not specified 2018-02-26 criteria provided, single submitter clinical testing Variant summary: APC c.2297C>T (p.Ala766Val) results in a non-conservative amino acid change located in the Armadillo-associated region of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This frequency is not significantly higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (8.1e-06 vs 7.1e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2297C>T in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034407 SCV000043114 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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