ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5866A>G (p.Ile1956Val) (rs749597014)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587771 SCV000293658 uncertain significance not provided 2015-12-08 criteria provided, single submitter clinical testing This variant is denoted APC c.5866A>G at the cDNA level, p.Ile1956Val (I1956V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ile1956Val 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 Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Ile1956Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the 20-aa beta-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). 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 Ile1956Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587771 SCV000694087 uncertain significance not provided 2016-07-15 criteria provided, single submitter clinical testing Variant summary: The APC c.5866A>G (p.Ile1956Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/120888 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000236514 SCV000731487 uncertain significance not specified 2017-04-17 criteria provided, single submitter clinical testing The p.Ile1956Val variant in APC has not been previously reported in the literatu re in individuals with familial adenomatous polyposis or other APC-associated di sorders, but has been reported in ClinVar (Variation ID 246202). This variant ha s been identified in 1/15286 of African chromosomes by the Genome Aggregation Da tabase (ExAC, http://gnomad.broadinstitute.org; dbSNP rs749597014). Computationa l prediction tools and conservation analysis do not provide strong support for o r against an impact to the protein. In summary, the clinical significance of the p.Ile1956Val variant is uncertain.
Invitae RCV000646438 SCV000768210 uncertain significance Familial adenomatous polyposis 1 2018-02-25 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1956 of the APC protein (p.Ile1956Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs749597014, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 246202). 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 disruptive, 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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