Submissions for variant NM_000038.6(APC):c.5060G>A (p.Arg1687Gln)

gnomAD frequency: 0.00002  dbSNP: rs779068685

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003651883	SCV000552709	benign	Familial adenomatous polyposis 1	2024-01-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000482697	SCV000566275	uncertain significance	not provided	2018-04-10	criteria provided, single submitter	clinical testing	This variant is denoted APC c.5060G>A at the cDNA level, p.Arg1687Gln (R1687Q) 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 pathogenic or benign. APC Arg1687Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the SAMP repeats/axin binding domain and the 20-aa repeat beta-catenin down-regulating domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Arg1687Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000580947	SCV000681703	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 1687 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 4/249722 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	RCV000482697	SCV001133342	uncertain significance	not provided	2019-02-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580947	SCV001185378	likely benign	Hereditary cancer-predisposing syndrome	2022-01-03	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293489	SCV001482069	uncertain significance	not specified	2021-02-08	criteria provided, single submitter	clinical testing	Variant summary: APC c.5060G>A (p.Arg1687Gln) results in a 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 1.6e-05 in 249722 control chromosomes, predominantly at a frequency of 8.7e-05 within the Latino subpopulation in the gnomAD database. 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.5060G>A 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 (n=4) or benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000580947	SCV002535020	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-11	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003392285	SCV004111778	uncertain significance	APC-related condition	2023-03-30	criteria provided, single submitter	clinical testing	The APC c.5060G>A variant is predicted to result in the amino acid substitution p.Arg1687Gln. This variant has been reported as a somatic change in two gastric tumors (Table S3, Koh et al. 2019. PubMed ID: 30239046). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112176351-G-A). It is interpreted as uncertain significance by the majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/411515/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.