ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4906G>T (p.Asp1636Tyr) (rs730882128)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000161934 SCV000211919 uncertain significance Familial adenomatous polyposis 1 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 1636 of the APC protein (p.Asp1636Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 183069). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000236412 SCV000293034 uncertain significance not provided 2016-02-25 criteria provided, single submitter clinical testing This variant is denoted APC c.4906G>T at the cDNA level, p.Asp1636Tyr (D1636Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAT>TAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Asp1636Tyr 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 Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Asp1636Tyr occurs at a position where amino acids with properties similar to Aspartic Acid are tolerated across species and is located in the SAMP repeats/axin binding domain and within a Beta-catenin down-regulating 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 Asp1636Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000161934 SCV000488556 uncertain significance Familial adenomatous polyposis 1 2016-04-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000568367 SCV000667626 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000568367 SCV000908552 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-09 criteria provided, single submitter clinical testing

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