Submissions for variant NM_000038.6(APC):c.6127A>G (p.Ile2043Val)

gnomAD frequency: 0.00001  dbSNP: rs876660233

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217035	SCV000277480	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-21	criteria provided, single submitter	clinical testing	The p.I2043V variant (also known as c.6127A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 6127. The isoleucine at codon 2043 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV003650502	SCV000552635	uncertain significance	Familial adenomatous polyposis 1	2023-11-02	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 2043 of the APC protein (p.Ile2043Val). This variant is present in population databases (no rsID available, 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: 233160). 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.
Color Diagnostics, LLC DBA Color Health	RCV000217035	SCV000904771	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 2043 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 2/282286 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780836	SCV000918436	uncertain significance	not specified	2018-04-06	criteria provided, single submitter	clinical testing	Variant summary: APC c.6127A>G (p.Ile2043Val) results in a conservative amino acid change located in the SAMP domain of 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 7.2e-06 in 276604 control chromosomes. This frequency is not higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (7.2e-06 vs 7.1e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.6127A>G in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284244	SCV001469922	uncertain significance	not provided	2020-02-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001284244	SCV002031175	uncertain significance	not provided	2021-12-06	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: 18199528)
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000217035	SCV004228141	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-03	criteria provided, single submitter	clinical testing