Submissions for variant NM_000038.6(APC):c.2834_2835delinsTT (p.Arg945Ile)

dbSNP: rs786204162

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002291586	SCV000218824	uncertain significance	Familial adenomatous polyposis 1	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 945 of the APC protein (p.Arg945Ile). This variant is present in population databases (rs786204162, gnomAD 0.004%). 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: 188226). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV000215714	SCV000274062	likely benign	Hereditary cancer-predisposing syndrome	2021-03-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	RCV000215714	SCV000681555	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with isoleucine at codon 945 of the APC protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291586	SCV002584647	uncertain significance	Familial adenomatous polyposis 1	2022-07-07	criteria provided, single submitter	clinical testing	The APC c.2834_2835delinsTT (p.Arg945Ile) change results from deletion of GG and insertion of TT to cause the substitution of the arginine residue for an isoleucine residue at codon 945. This change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). In silico analysis using PROVEAN predicts a deleterious effect of this variant on protein function (PMID: 23056405), but to our knowledge functional studies have not been performed. This variant has been reported in an unaffected individual with family history of colorectal cancer and colon polyps (PMID: 30374176). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV002292479	SCV002586069	uncertain significance	not provided	2022-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV002292479	SCV004035617	uncertain significance	not provided	2023-09-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25925381)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002292479	SCV004221490	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing	To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00016 (4/25114 chromosomes in European (Finnish) subpopulation, 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.