Submissions for variant NM_000038.6(APC):c.1495C>G (p.Arg499Gly)

gnomAD frequency: 0.00003  dbSNP: rs137854580

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472427	SCV000552766	likely benign	Familial adenomatous polyposis 1	2024-08-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000564391	SCV000672537	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-01	criteria provided, single submitter	clinical testing	The p.R499G variant (also known as c.1495C>G), located in coding exon 11 of the APC gene, results from a C to G substitution at nucleotide position 1495. The arginine at codon 499 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000472427	SCV000786129	uncertain significance	Familial adenomatous polyposis 1	2018-03-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034403	SCV000888718	uncertain significance	not provided	2018-05-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564391	SCV000911387	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 499 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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, but has been found in individuals selected for non-cancer phenotypes (PMID: 25203624, 22703879). This variant has been identified in 7/251260 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	RCV000780856	SCV000918474	uncertain significance	not specified	2019-10-31	criteria provided, single submitter	clinical testing	Variant summary: APC c.1495C>G (p.Arg499Gly) results in a non-conservative amino acid change located in the Armadillo repeats of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251260 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1495C>G has not been reported in the literature in individuals affected with Familial Adenomatous Polyposis nor, to our knowledge, has experimental evidence demonstrating an impact on protein function been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000472427	SCV004018838	uncertain significance	Familial adenomatous polyposis 1	2023-02-23	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000472427	SCV004209598	uncertain significance	Familial adenomatous polyposis 1	2023-08-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996158	SCV004837413	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 499 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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, but has been found in individuals selected for non-cancer phenotypes (PMID: 25203624, 22703879). This variant has been identified in 7/251260 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.
GeneDx	RCV000034403	SCV005332881	uncertain significance	not provided	2024-02-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has 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: 22703879, 18199528)
Fulgent Genetics, Fulgent Genetics	RCV005042106	SCV005667825	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2024-01-22	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034403	SCV000043110	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.