Submissions for variant NM_000038.6(APC):c.3607G>C (p.Gly1203Arg)

dbSNP: rs1057518472

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003651872	SCV000552642	uncertain significance	Familial adenomatous polyposis 1	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1203 of the APC protein (p.Gly1203Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 411470). 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	RCV000479172	SCV000564571	uncertain significance	not provided	2015-03-01	criteria provided, single submitter	clinical testing	This variant is denoted APC c.3607G>C at the cDNA level, p.Gly1203Arg (G1203R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>CGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Gly1203Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Gly1203Arg occurs at a position that is poorly conserved across species and is located in a region predicted to be responsible for protein downregulation by ubiquitination (UniProt) but does not fall into any known functional domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Gly1203Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000568797	SCV000667552	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-24	criteria provided, single submitter	clinical testing	The p.G1203R variant (also known as c.3607G>C), located in coding exon 15 of the APC gene, results from a G to C substitution at nucleotide position 3607. The glycine at codon 1203 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is poorly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264493	SCV001442671	uncertain significance	not specified	2020-10-29	criteria provided, single submitter	clinical testing	Variant summary: APC c.3607G>C (p.Gly1203Arg) 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 was absent in 250592 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3607G>C has been reported in the literature in one individual affected with breast cancer (Tung_2014). The report does 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.