ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4213G>A (p.Val1405Ile) (rs761966904)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227053 SCV000282752 uncertain significance Familial adenomatous polyposis 1 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1405 of the APC protein (p.Val1405Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs761966904, ExAC 0.001%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 236597). 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.
GeneDx RCV000586529 SCV000572362 uncertain significance not provided 2016-11-28 criteria provided, single submitter clinical testing This variant is denoted APC c.4213G>A at the cDNA level, p.Val1405Ile (V1405I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Val1405Ile 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 Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. APC Val1405Ile occurs at a position that is conserved across species and is located in the 20-amino acid 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 Val1405Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569595 SCV000672504 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000586529 SCV000694046 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The APC c.4213G>A (p.Val1405Ile) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/121302 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence becomes available.

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