ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2485A>G (p.Thr829Ala) (rs768810807)

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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 RCV000223345 SCV000276231 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: in silico models in agreement (benign),Insufficient or Conflicting Evidence
GeneDx RCV000766315 SCV000566818 uncertain significance not provided 2016-11-14 criteria provided, single submitter clinical testing This variant is denoted APC c.2485A>G at the cDNA level, p.Thr829Ala (T829A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. However, this variant was identified in at least one pancreatic neoplasm on whole exome sequencing (Jiao 2014). APC Thr829Ala 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 Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Thr829Ala occurs at a position that is conserved in mammals and is not located in a known functional domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Thr829Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480119 SCV000600059 uncertain significance not specified 2017-03-09 criteria provided, single submitter clinical testing
Color RCV000223345 SCV000681526 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Invitae RCV000698735 SCV000827417 uncertain significance Familial adenomatous polyposis 1 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 829 of the APC protein (p.Thr829Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs768810807, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 232173). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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