ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4055T>C (p.Val1352Ala) (rs528724202)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129128 SCV000183846 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Other data supporting pathogenic classification
GeneDx RCV000483615 SCV000568279 uncertain significance not specified 2016-09-08 criteria provided, single submitter clinical testing This variant is denoted APC c.4055T>C at the cDNA level, p.Val1352Ala (V1352A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). This variant was observed in one individual with 11-99 colorectal adenomas in a cohort of 691 patients with colorectal polyps and was absent from 969 healthy controls (Azzopardi 2008). APC Val1352Ala was not observed at significant allele frequency in 1000 Genomes. Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. APC Val1352Ala occurs at a position that is conserved across species and is located in the 20-aa repeat B-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 Val1352Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483615 SCV000600093 uncertain significance not specified 2017-03-25 criteria provided, single submitter clinical testing
Color RCV000129128 SCV000686963 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
Invitae RCV000646425 SCV000768197 uncertain significance Familial adenomatous polyposis 1 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1352 of the APC protein (p.Val1352Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs528724202, ExAC 0.05%). This variant has been reported in individuals affected with colorectal adenomas, familial non-medullary thyroid cancer, and colorectal cancer (PMID: 18199528, 26530882, 27121310). ClinVar contains an entry for this variant (Variation ID: 140890). 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.
Counsyl RCV000646425 SCV000785305 uncertain significance Familial adenomatous polyposis 1 2017-07-05 criteria provided, single submitter clinical testing

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