Submissions for variant NM_000038.6(APC):c.7166G>A (p.Ser2389Asn)

gnomAD frequency: 0.00002  dbSNP: rs779287035

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527861	SCV000647696	uncertain significance	Familial adenomatous polyposis 1	2025-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2389 of the APC protein (p.Ser2389Asn). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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: 470080). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Ambry Genetics	RCV000564175	SCV000667356	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-02	criteria provided, single submitter	clinical testing	The p.S2389N variant (also known as c.7166G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 7166. The serine at codon 2389 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586700	SCV000694109	uncertain significance	not provided	2017-07-03	criteria provided, single submitter	clinical testing	Variant summary: The c.7166G>A (p.Ser2389Asn) in APC gene is a missense variant involves a mildly conserved nucleotide and 3/5 in silico tools predict deleterious outcome. The variant is located within the basic domain, however no functional studies supporting deleterious outcome of this alteration on the protein function have been published at the time of evaluation. The variant is absent from the control population dataset of ExAC, but is present at a low frequency in gnomAD (0.000004081; 1/245052 chrs tested), which does not exceed the maximal expected allele frequency for a disease causing allele in APC gene (0.00007). To our knowledge, the variant has not been reported in affected individuals via published reports nor has it been cited by reputable databases/clinical laboratories. Taken together, the variant was classified as VUS, until new information becomes available.
Fulgent Genetics, Fulgent Genetics	RCV000765790	SCV000897179	uncertain significance	Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000564175	SCV000905274	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 2389 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 APC-related disorders in the literature. This variant has been identified in 1/250312 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586700	SCV002046430	uncertain significance	not provided	2020-11-17	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002527861	SCV004191417	uncertain significance	Familial adenomatous polyposis 1	2023-09-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999424	SCV004843510	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with asparagine at codon 2389 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 APC-related disorders in the literature. This variant has been identified in 1/250312 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.