ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2414G>A (p.Arg805Gln)

gnomAD frequency: 0.00001  dbSNP: rs200593940
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003651896 SCV000552768 uncertain significance Familial adenomatous polyposis 1 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 805 of the APC protein (p.Arg805Gln). This variant is present in population databases (rs200593940, gnomAD 0.005%). This missense change has been observed in individual(s) with adrenocortical carcinoma (PMID: 32088909). ClinVar contains an entry for this variant (Variation ID: 411558). 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 RCV000491212 SCV000579807 likely benign Hereditary cancer-predisposing syndrome 2021-04-05 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 RCV000491212 SCV000681520 uncertain significance Hereditary cancer-predisposing syndrome 2022-04-05 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 805 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 32984025), or adrenocortical carcinoma (PMID: 32088909). This variant has been identified in 4/282254 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.
Mendelics RCV000468198 SCV001136893 uncertain significance Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
GeneDx RCV001549488 SCV001769645 uncertain significance not provided 2020-11-12 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32984025, 32088909, 27329244, 26991699, 27149842)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003479129 SCV004223487 uncertain significance not specified 2023-11-08 criteria provided, single submitter clinical testing Variant summary: APC c.2414G>A (p.Arg805Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-06 in 1614008 control chromosomes (gnomAD v4). This frequency is not significantly higher than estimated for a pathogenic variant in APC causing Familial Adenomatous Polyposis (8.7e-06 vs 7.1e-05), allowing no conclusion about variant significance. c.2414G>A has been reported in the literature in individuals affected with adrenocortical carcinoma (e.g., Gagnon_2020) and rectal cancer (e.g., Xu_2020). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32088909, 32984025). Six submitters have reported this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 5; likely benign, n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance.
3DMed Clinical Laboratory Inc RCV000677778 SCV000803934 uncertain significance Neoplasm of the liver 2018-05-21 no assertion criteria provided clinical testing

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