ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6136G>A (p.Ala2046Thr) (rs770406711)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164449 SCV000215091 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000411350 SCV000488440 uncertain significance Familial adenomatous polyposis 1 2016-03-29 criteria provided, single submitter clinical testing
Invitae RCV000411350 SCV000552458 uncertain significance Familial adenomatous polyposis 1 2018-09-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 2046 of the APC protein (p.Ala2046Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs770406711, ExAC 0.01%). This variant has been reported in an individual with colorectal cancer (PMID: 28195393). ClinVar contains an entry for this variant (Variation ID: 185089). 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 is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000759436 SCV000564578 uncertain significance not provided 2015-02-03 criteria provided, single submitter clinical testing This variant is denoted APC c.6136G>A at the cDNA level, p.Ala2046Thr (A2046T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ala2046Thr 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 Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Ala2046Thr occurs at a position that is highly conserved across species and is located within the SAMP repeats/axin binding 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 Ala2046Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000164449 SCV000681785 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759436 SCV000888755 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Mendelics RCV000411350 SCV001136929 uncertain significance Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing

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