Submissions for variant NM_000038.6(APC):c.3368A>C (p.Gln1123Pro)

gnomAD frequency: 0.00004  dbSNP: rs587779789

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115081	SCV000148990	uncertain significance	not provided	2023-08-23	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: 25742471, 18199528)
Invitae	RCV003650369	SCV000552623	uncertain significance	Familial adenomatous polyposis 1	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1123 of the APC protein (p.Gln1123Pro). This variant is present in population databases (rs587779789, gnomAD 0.02%). 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: 127287). 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.
Ambry Genetics	RCV000569678	SCV000667569	likely benign	Hereditary cancer-predisposing syndrome	2021-11-17	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.
PreventionGenetics, part of Exact Sciences	RCV000115081	SCV000805393	uncertain significance	not provided	2018-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000569678	SCV000911735	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-07	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with proline at codon 1123 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 hereditary cancer in the literature. This variant has been identified in 4/31402 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	RCV001251414	SCV001427004	uncertain significance	not specified	2020-07-30	criteria provided, single submitter	clinical testing	Variant summary: APC c.3368A>C (p.Gln1123Pro) results in a non-conservative amino acid change in 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 0.00013 in 31402 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3368A>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001251414	SCV002064791	uncertain significance	not specified	2020-09-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.3368A>C, in exon 16 that results in an amino acid change, p.Gln1123Pro. This sequence change does not appear to have been previously described in patients with APC-related disorders and has been described in the gnomAD database in four individuals with an overall population frequency of 0.013% (dbSNP rs587779789). The p.Gln1123Pro change affects a highly conserved amino acid residue located in a domain of the APC protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gln1123Pro substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gln1123Pro change remains unknown at this time.