ClinVar Miner

Submissions for variant NM_000038.6(APC):c.596C>T (p.Ala199Val) (rs748193367)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236321 SCV000293792 uncertain significance not provided 2016-01-05 criteria provided, single submitter clinical testing This variant is denoted APC c.596C>T at the cDNA level, p.Ala199Val (A199V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ala199Val 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 Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Ala199Val occurs at a position that is conserved across species and is located in a coiled-coil motif within a Leucine-rich region (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Ala199Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563434 SCV000667379 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000563434 SCV000681771 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Invitae RCV000698294 SCV000826951 uncertain significance Familial adenomatous polyposis 1 2018-08-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 199 of the APC protein (p.Ala199Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs748193367, ExAC 0.02%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 246301). 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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