Submissions for variant NM_000038.6(APC):c.4765C>G (p.Arg1589Gly)

dbSNP: rs72541813

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131191	SCV000186141	likely benign	Hereditary cancer-predisposing syndrome	2019-03-20	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.
GeneDx	RCV000211915	SCV000209469	uncertain significance	not provided	2022-12-19	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with multiple adenomatous colon polyps, thyroid cancer, and sarcoma (Urso et al., 2013; Ballinger et al., 2016; Yehia et al., 2018); This variant is associated with the following publications: (PMID: 18199528, 27498913, 22773231, 27156442, 29684080, 30122538)
Invitae	RCV003315903	SCV000282762	likely benign	Familial adenomatous polyposis 1	2024-01-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000232313	SCV000489580	uncertain significance	Familial adenomatous polyposis 1	2016-10-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131191	SCV000681683	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 1589 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 been reported in individuals affected with multiple colorectal adenomas (PMID: 22773231), thyroid cancer (PMID: 29684080), and sarcoma (PMID: 27498913), but also in control individuals (PMID: 18199528). This variant has been identified in 19/282472 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.
PreventionGenetics, part of Exact Sciences	RCV000211915	SCV000805412	uncertain significance	not provided	2017-03-27	criteria provided, single submitter	clinical testing
Mendelics	RCV003492615	SCV000838121	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001157157	SCV001318704	uncertain significance	APC-Associated Polyposis Disorders	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000211915	SCV001469308	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00011 (14/128838 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with thyroid cancer (PMID: 29684080 (2018)) and colorectal polyps (PMID: 22773231 (2013)), as well as healthy individuals (PMIDs: 18199528 (2008) and 30267214 (2018)). 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Genetic Services Laboratory, University of Chicago	RCV001818321	SCV002069705	uncertain significance	not specified	2020-04-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.4765C>G, in exon 16 that results in an amino acid change, p.Arg1589Gly. 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 with a low population frequency of 0.0067% (dbSNP rs72541813). The p.Arg1589Gly change affects a moderately conserved amino acid residue located in a domain of the APC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg1589Gly substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg1589Gly change remains unknown at this time.
Sema4, Sema4	RCV000131191	SCV002532654	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-05	criteria provided, single submitter	curation
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003325188	SCV004012943	uncertain significance	Diffuse midline glioma, H3 K27-altered	2022-05-16	criteria provided, single submitter	research
Myriad Genetics, Inc.	RCV003315903	SCV004018609	likely benign	Familial adenomatous polyposis 1	2023-02-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818321	SCV004025068	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818321	SCV004030042	uncertain significance	not specified	2023-07-06	criteria provided, single submitter	clinical testing	Variant summary: APC c.4765C>G (p.Arg1589Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251116 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in APC causing Familial Adenomatous Polyposis (6.8e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.4765C>G has been reported in the literature in individuals affected with a personal or family history of colorectal polyposis without strong evidence of causality (Poliani_2022, Urso_2013). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36356413, 22773231). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=9) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
GenomeConnect - Invitae Patient Insights Network	RCV001157157	SCV004037530	not provided	APC-Associated Polyposis Disorders		no assertion provided	phenotyping only	Variant classified as Likely benign and reported on 11-14-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.