Submissions for variant NM_000038.6(APC):c.647G>A (p.Arg216Gln)

gnomAD frequency: 0.00003  dbSNP: rs76685252

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003534462	SCV000218927	uncertain significance	Familial adenomatous polyposis 1	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 216 of the APC protein (p.Arg216Gln). This variant is present in population databases (rs76685252, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer, breast cancer (PMID: 18199528, 28135145, 35264596). ClinVar contains an entry for this variant (Variation ID: 188275). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Illumina Laboratory Services, Illumina	RCV000364207	SCV000451984	likely benign	APC-Associated Polyposis Disorders	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000480784	SCV000568267	uncertain significance	not provided	2022-11-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer or adenomas (Azzopardi et al., 2008; Minde et al., 2011; Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 21859464, 28748566, 28873162, 27329244, 18199528, 26332594, 28135145)
Ambry Genetics	RCV000563625	SCV000672497	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	The p.R216Q variant (also known as c.647G>A), located in coding exon 6 of the APC gene, results from a G to A substitution at nucleotide position 647. The arginine at codon 216 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in a cohort of 691 North Americans, in one individual with 11-99 colorectal adenomas (Azzopardi D et al. Cancer Res. 2008 Jan;68:358-63), and has also been reported in a cohort of individuals with unselected colorectal cancer (Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35:1086-1095). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000168256	SCV000785219	uncertain significance	Familial adenomatous polyposis 1	2017-06-06	criteria provided, single submitter	clinical testing
Mendelics	RCV003491922	SCV000838066	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000563625	SCV000911013	likely benign	Hereditary cancer-predisposing syndrome	2016-06-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480784	SCV001133356	uncertain significance	not provided	2019-08-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000168256	SCV004018933	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	RCV000168256	SCV004196422	uncertain significance	Familial adenomatous polyposis 1	2023-10-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987392	SCV004804237	uncertain significance	not specified	2024-01-02	criteria provided, single submitter	clinical testing	Variant summary: APC c.647G>A (p.Arg216Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 250290 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in APC causing Familial Adenomatous Polyposis (4e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.647G>A has been reported in the literature in individuals affected with colorectal cancer and breast cancer (examples:Azzopardi_2008, Yurgelun_2017, Guindalini_2022). These report(s) 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: 18199528, 35264596, 21859464, 36243179, 26332594, 28135145). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS n=7, likely benign n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.