ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1318G>A (p.Ala440Thr) (rs1064793023)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590604 SCV000564563 uncertain significance not provided 2017-11-16 criteria provided, single submitter clinical testing This variant is denoted APC c.1318G>A at the cDNA level, p.Ala440Thr (A440T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ala440Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Ala440Thr is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available information, it is unclear whether APC Ala440Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590604 SCV000693991 uncertain significance not provided 2017-02-16 criteria provided, single submitter clinical testing Variant summary: The APC c.1318G>A (p.Ala440Thr) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120198 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000807754 SCV000947825 uncertain significance Familial adenomatous polyposis 1 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 440 of the APC protein (p.Ala440Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine 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: 418008). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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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