ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7117A>G (p.Met2373Val) (rs879254221)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236661 SCV000293873 uncertain significance not provided 2017-11-21 criteria provided, single submitter clinical testing This variant is denoted APC c.7117A>G at the cDNA level, p.Met2373Val (M2373V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Met2373Val was not observed large population cohorts (Lek 2016). Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Met2373Val is located in the Basic 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 Met2373Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000549607 SCV000647692 uncertain significance Familial adenomatous polyposis 1 2018-09-08 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 2373 of the APC protein (p.Met2373Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. 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: 246357). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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