ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4669A>G (p.Ile1557Val) (rs763578917)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589170 SCV000292773 uncertain significance not provided 2018-11-23 criteria provided, single submitter clinical testing This variant is denoted APC c.4669A>G at the cDNA level, p.Ile1557Val (I1557V) 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 a pathogenic or benign germline variant. APC Ile1557Val was observed at an allele frequency of 0.02% (19/125688) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the beta-catenin down-regulating domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Ile1557Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000469610 SCV000552671 likely benign Familial adenomatous polyposis 1 2020-11-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491300 SCV000579816 likely benign Hereditary cancer-predisposing syndrome 2019-03-19 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Other strong data supporting benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589170 SCV000694056 likely benign not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The APC c.4669A>G (p.Ile1557Val) variant involves the alteration of a non-conserved nucleotide, which is not located in any known domain (InterPro). 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 14/120490 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0001962 (13/66264). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. 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. Taken together, this variant is classified as likely benign.
Color Health, Inc RCV000491300 SCV000910831 likely benign Hereditary cancer-predisposing syndrome 2017-01-04 criteria provided, single submitter clinical testing

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