Submissions for variant NM_000038.6(APC):c.8447G>A (p.Arg2816Gln)

gnomAD frequency: 0.00001  dbSNP: rs769704991

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485330	SCV000567650	uncertain significance	not provided	2015-08-12	criteria provided, single submitter	clinical testing	This variant is denoted APC c.8447G>A at the cDNA level, p.Arg2816Gln (R2816Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism. However, this variant has been reported as a somatic variant in a colon tumor cell line (Seshagiri 2012, Bourgon 2014). APC Arg2816Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Arg2816Gln occurs at a position that is conserved across species and is located within a serine-rich region of the HDLG domain (Azzopardi 2008, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Arg2816Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000571556	SCV000667618	likely benign	Hereditary cancer-predisposing syndrome	2022-04-19	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	RCV003470546	SCV001236030	uncertain significance	Familial adenomatous polyposis 1	2024-01-25	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 2816 of the APC protein (p.Arg2816Gln). This variant is present in population databases (rs769704991, gnomAD 0.007%). 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: 419681). 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	RCV000571556	SCV001344498	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 2816 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 3/237678 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.
Baylor Genetics	RCV003470546	SCV004200342	uncertain significance	Familial adenomatous polyposis 1	2023-09-21	criteria provided, single submitter	clinical testing