ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4073C>T (p.Ala1358Val) (rs730881249)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235095 SCV000209522 uncertain significance not specified 2016-11-29 criteria provided, single submitter clinical testing This variant is denoted APC c.4073C>T at the cDNA level, p.Ala1358Val (A1358V) 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 Ala1358Val 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 Ala1358Val occurs at a position that is conserved across species and is located within the 20-amino acid repeat of the beta-Catenin down-regulating 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 Ala1358Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159553 SCV000214495 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
University of Washington Department of Laboratory Medicine,University of Washington RCV000210103 SCV000266141 uncertain significance Colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000227806 SCV000282749 uncertain significance Familial adenomatous polyposis 1 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1358 of the APC protein (p.Ala1358Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs730881249, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual with colon polyps (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 181805). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C25"). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235095 SCV000600095 uncertain significance not specified 2017-06-09 criteria provided, single submitter clinical testing
Color RCV000159553 SCV000681646 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000998414 SCV001154467 uncertain significance not provided 2018-05-01 criteria provided, single submitter clinical testing

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