ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2474A>G (p.Tyr825Cys) (rs186641437)

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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 RCV000220641 SCV000277195 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000485918 SCV000567149 uncertain significance not provided 2016-10-20 criteria provided, single submitter clinical testing This variant is denoted APC c.2474A>G at the cDNA level, p.Tyr825Cys (Y825C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Tyr825Cys was not observed at a significant allele frequency in 1000 Genomes. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Tyr825Cys occurs at a position that is conserved in mammals and is not located in a known functional domain (Azzopardi 2008). 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 Tyr825Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000220641 SCV000686895 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-26 criteria provided, single submitter clinical testing
Invitae RCV000646251 SCV000768019 uncertain significance Familial adenomatous polyposis 1 2018-11-27 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 825 of the APC protein (p.Tyr825Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs186641437, ExAC 0.02%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 232924). 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, 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.
Fulgent Genetics,Fulgent Genetics RCV000764563 SCV000895651 uncertain significance Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing

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