Submissions for variant NM_000038.6(APC):c.4207A>G (p.Ser1403Gly)

gnomAD frequency: 0.00001  dbSNP: rs759317924

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508542	SCV000600096	uncertain significance	not specified	2017-06-16	criteria provided, single submitter	clinical testing
Invitae	RCV003535800	SCV000768081	uncertain significance	Familial adenomatous polyposis 1	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1403 of the APC protein (p.Ser1403Gly). This variant is present in population databases (rs759317924, gnomAD 0.003%). 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: 438878). 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.
Color Diagnostics, LLC DBA Color Health	RCV000772036	SCV000905039	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 1403 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). 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 been identified in 3/251032 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.
Ambry Genetics	RCV000772036	SCV001183744	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-02	criteria provided, single submitter	clinical testing	The p.S1403G variant (also known as c.4207A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 4207. The serine at codon 1403 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly 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.
GeneDx	RCV001775833	SCV002013729	uncertain significance	not provided	2019-11-22	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV000772036	SCV002531904	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	curation