Submissions for variant NM_000038.6(APC):c.2533C>T (p.Arg845Cys)

dbSNP: rs1554084249

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000574291	SCV000672502	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	The p.R845C variant (also known as c.2533C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 2533. The arginine at codon 845 is replaced by cysteine, an amino acid with highly 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.
Invitae	RCV002530325	SCV001233638	uncertain significance	Familial adenomatous polyposis 1	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 845 of the APC protein (p.Arg845Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 485094). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000574291	SCV001359496	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 845 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153743	SCV003843769	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002530325	SCV004204830	uncertain significance	Familial adenomatous polyposis 1	2023-06-21	criteria provided, single submitter	clinical testing