ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2026A>G (p.Ile676Val)

gnomAD frequency: 0.00002  dbSNP: rs745529713
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003535601 SCV000282709 uncertain significance Familial adenomatous polyposis 1 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 676 of the APC protein (p.Ile676Val). This variant is present in population databases (rs745529713, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal or pancreatic cancer (PMID: 32980694, 33193653). ClinVar contains an entry for this variant (Variation ID: 236567). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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.
Ambry Genetics RCV000574116 SCV000675892 likely benign Hereditary cancer-predisposing syndrome 2023-02-03 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health RCV000574116 SCV000681502 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-08 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 676 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual from family affected with colorectal cancer that did not have polyposis (PMID: 33193653). This variant has been identified in 6/250776 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Preventiongenetics, part of Exact Sciences RCV000679050 SCV000805376 uncertain significance not provided 2016-11-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679050 SCV000888726 uncertain significance not provided 2018-04-11 criteria provided, single submitter clinical testing
GeneDx RCV000679050 SCV001777714 uncertain significance not provided 2020-01-28 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33193653)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002267974 SCV002550596 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing
Baylor Genetics RCV002516262 SCV004205270 uncertain significance Familial adenomatous polyposis 1 2023-06-20 criteria provided, single submitter clinical testing

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