ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7922A>C (p.Lys2641Thr) (rs879254231)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235631 SCV000293917 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing This variant is denoted APC c.7922A>C at the cDNA level, p.Lys2641Thr (K2641T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Lys2641Thr was not observed in large population cohorts (Lek 2016). Since Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Lys2641Thr is located in the EB1 binding domain (Azzopardi 2008). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Lys2641Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000575151 SCV000667530 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000809703 SCV000949871 uncertain significance Familial adenomatous polyposis 1 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 2641 of the APC protein (p.Lys2641Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. 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: 246385). 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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