ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3536A>G (p.Tyr1179Cys) (rs777568434)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486102 SCV000564570 uncertain significance not provided 2017-12-04 criteria provided, single submitter clinical testing This variant is denoted APC c.3536A>G at the cDNA level, p.Tyr1179Cys (Y1179C) 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 Tyr1179Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Tyr1179Cys is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether APC Tyr1179Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491910 SCV000579806 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Invitae RCV000694809 SCV000823271 uncertain significance Familial adenomatous polyposis 1 2018-08-25 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1179 of the APC protein (p.Tyr1179Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs777568434, ExAC 0.002%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 418011). 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 C15"). 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.

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