Submissions for variant NM_000038.6(APC):c.4249A>C (p.Ile1417Leu)

gnomAD frequency: 0.00006  dbSNP: rs200166878

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003743579	SCV000166036	uncertain significance	Familial adenomatous polyposis 1	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1417 of the APC protein (p.Ile1417Leu). This variant is present in population databases (rs200166878, gnomAD 0.03%). 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: 135701). 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.
GeneDx	RCV000235379	SCV000292866	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	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: 21157497, 30981987, 30171174, 18199528)
Ambry Genetics	RCV000575531	SCV000667258	likely benign	Hereditary cancer-predisposing syndrome	2020-11-24	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	RCV000575531	SCV000681659	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-18	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 1417 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 15/282336 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235379	SCV000888744	uncertain significance	not provided	2023-08-11	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported as a germline variant in individuals with APC-related conditions in the published literature. The frequency of this variant in the general population, 0.00028 (10/35416 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000122779	SCV001136909	uncertain significance	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193569	SCV001362482	uncertain significance	not specified	2022-04-14	criteria provided, single submitter	clinical testing	Variant summary: APC c.4249A>C (p.Ile1417Leu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 250950 control chromosomes, predominantly at a frequency of 0.00029 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4.06 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, c.4249A>C has not been reported in individuals with Familial Adenomatous Polyposis and no experimental evidence demonstrating an impact on protein function has been reported in the literature. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000235379	SCV004026233	uncertain significance	not provided	2021-08-10	criteria provided, single submitter	clinical testing	PP3