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

Total submissions: 5

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