Submissions for variant NM_000038.6(APC):c.7273A>G (p.Ser2425Gly)

dbSNP: rs730881261

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159572	SCV000209547	uncertain significance	not provided	2014-08-06	criteria provided, single submitter	clinical testing	This variant is denoted APC c.7273A>G at the cDNA level, p.Ser2425Gly (S2425G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Ser2425Gly 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 Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Ser2425Gly occurs at a position that is moderately conserved across species and is located in the Helicase ATP-binding domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether APC Ser2425Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004567184	SCV000261585	uncertain significance	Familial adenomatous polyposis 1	2021-01-31	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 181820). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with glycine at codon 2425 of the APC protein (p.Ser2425Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine.
Color Diagnostics, LLC DBA Color Health	RCV001186726	SCV001353300	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-07	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 2425 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
Ambry Genetics	RCV001186726	SCV005139522	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-09	criteria provided, single submitter	clinical testing	The p.S2425G variant (also known as c.7273A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 7273. The serine at codon 2425 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV004806111	SCV005429295	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 2425 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
Fulgent Genetics, Fulgent Genetics	RCV005031671	SCV005667889	uncertain significance	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2024-06-21	criteria provided, single submitter	clinical testing