ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1876A>G (p.Thr626Ala) (rs771748555)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478621 SCV000570436 uncertain significance not provided 2016-05-26 criteria provided, single submitter clinical testing This variant is denoted APC c.1876A>G at the cDNA level, p.Thr626Ala (T626A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant was observed in one individual referred for clinical FAP testing (Kerr 2013). APC Thr626Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting 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 Thr626Ala occurs at a position that is conserved across species and is located within the Armadillo Region (Azzopardi 2008). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Thr626Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491486 SCV000579848 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000491486 SCV000681492 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-16 criteria provided, single submitter clinical testing
Invitae RCV000646308 SCV000768076 uncertain significance Familial adenomatous polyposis 1 2018-07-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 626 of the APC protein (p.Thr626Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs771748555, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual evaluated for familial adenomatous polyposis (FAP) (PMID: 23159591). ClinVar contains an entry for this variant (Variation ID: 421285). 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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