Submissions for variant NM_000038.6(APC):c.6196A>G (p.Arg2066Gly)

gnomAD frequency: 0.00001  dbSNP: rs786204043

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002228998	SCV000218527	uncertain significance	Familial adenomatous polyposis 1	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2066 of the APC protein (p.Arg2066Gly). This variant is present in population databases (rs786204043, gnomAD 0.002%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 188063). 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.
GeneDx	RCV001850371	SCV000568282	uncertain significance	not provided	2022-03-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in one individual with multiple colorectal polyps in published literature (Azzopardi 2008); This variant is associated with the following publications: (PMID: 21859464, 28526081, 18199528)
Counsyl	RCV000167881	SCV000784998	uncertain significance	Familial adenomatous polyposis 1	2017-03-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000483290	SCV001338209	uncertain significance	not specified	2020-02-24	criteria provided, single submitter	clinical testing	Variant summary: APC c.6196A>G (p.Arg2066Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250730 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6196A>G has been reported in the literature in at least one individual affected with colorectal adenomas (e.g. Azzopardi_2008). These report(s), however 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. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001523902	SCV001733638	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 2066 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 been reported in an individual affected with over 100 colorectal adenomas (PMID: 18199528). This variant has been identified in 2/282126 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.
CeGaT Center for Human Genetics Tuebingen	RCV001850371	SCV002497341	uncertain significance	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001523902	SCV002655038	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	clinical testing	The p.R2066G variant (also known as c.6196A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 6196. This alteration has been reported in a cohort of 691 North American patients with multiple colorectal adenomas (Azzopardi D et al. Cancer Res., 2008 Jan;68:358-63). The arginine at codon 2066 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV000167881	SCV004018922	uncertain significance	Familial adenomatous polyposis 1	2023-02-15	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	RCV000167881	SCV004199654	uncertain significance	Familial adenomatous polyposis 1	2023-10-05	criteria provided, single submitter	clinical testing