ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2957A>G (p.Tyr986Cys) (rs730881243)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159545 SCV000209509 uncertain significance not provided 2014-09-17 criteria provided, single submitter clinical testing This variant is denoted APC c.2957A>G at the cDNA level, p.Tyr986Cys (Y986C) 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 Tyr986Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Tyr986Cys occurs at a position that is highly conserved across species and is located in a region 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 Tyr986Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563690 SCV000667233 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000563690 SCV000686919 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-26 criteria provided, single submitter clinical testing
Invitae RCV000698608 SCV000827283 uncertain significance Familial adenomatous polyposis 1 2018-03-13 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 986 of the APC protein (p.Tyr986Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 181797). 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.

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