Submissions for variant NM_000038.6(APC):c.2945C>T (p.Ser982Leu)

gnomAD frequency: 0.00001  dbSNP: rs139773221

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561942	SCV000667453	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-06	criteria provided, single submitter	clinical testing	The p.S982L variant (also known as c.2945C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 2945. The serine at codon 982 is replaced by leucine, an amino acid with dissimilar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV003537116	SCV000834337	uncertain significance	Familial adenomatous polyposis 1	2023-08-10	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is present in population databases (rs139773221, gnomAD 0.002%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 982 of the APC protein (p.Ser982Leu). 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. 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. ClinVar contains an entry for this variant (Variation ID: 482283).
Color Diagnostics, LLC DBA Color Health	RCV000561942	SCV000906798	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 982 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). To our knowledge, functional studies have not been reported for this variant. In a colorectal case-control study, this variant was not reported in affected colorectal individuals but observed in a healthy control (PMID: 30267214). This variant has been identified in 3/282678 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	RCV001284349	SCV001470094	uncertain significance	not provided	2020-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000561942	SCV002531293	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-01	criteria provided, single submitter	curation
GeneDx	RCV001284349	SCV004040133	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a control individual and not in any colorectal cancer and/or polyposis patients (Rosenthal et al., 2018); This variant is associated with the following publications: (PMID: 28481359, 24367274, 29296220, 30267214)