ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7903A>G (p.Thr2635Ala) (rs886059799)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000261598 SCV000452051 uncertain significance APC-Associated Polyposis Disorders 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000463001 SCV000552550 uncertain significance Familial adenomatous polyposis 1 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 2635 of the APC protein (p.Thr2635Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. 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: 350423). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
GeneDx RCV000478957 SCV000565713 uncertain significance not provided 2016-09-06 criteria provided, single submitter clinical testing This variant is denoted APC c.7903A>G at the cDNA level, p.Thr2635Ala (T2635A) 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. APC Thr2635Ala 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 Thr2635Ala occurs at a position that is not conserved and is within the EB1 binding domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether APC Thr2635Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575871 SCV000667381 likely benign Hereditary cancer-predisposing syndrome 2017-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000575871 SCV000903486 likely benign Hereditary cancer-predisposing syndrome 2016-06-21 criteria provided, single submitter clinical testing

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