Submissions for variant NM_000038.6(APC):c.4349G>A (p.Arg1450Gln)

dbSNP: rs587782678

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132104	SCV000187169	likely benign	Hereditary cancer-predisposing syndrome	2019-03-27	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.
Invitae	RCV002514750	SCV000647512	uncertain significance	Familial adenomatous polyposis 1	2024-01-21	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 1450 of the APC protein (p.Arg1450Gln). This variant is present in population databases (rs587782678, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 142731). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265621	SCV000694051	uncertain significance	not specified	2022-05-13	criteria provided, single submitter	clinical testing	Variant summary: APC c.4349G>A (p.Arg1450Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251192 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4349G>A has been reported in the literature in individuals affected with colorectal cancer and esophageal cancer (Schell_2016, Visser_2017) without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three laboratories classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000132104	SCV000906433	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1450 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 not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 2/251192 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.
GeneDx	RCV000590671	SCV001805077	uncertain significance	not provided	2021-06-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533, 18199528, 27499925, 27882345)