Submissions for variant NM_000038.6(APC):c.1553C>T (p.Thr518Met)

gnomAD frequency: 0.00005  dbSNP: rs371453363

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221284	SCV000275913	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-14	criteria provided, single submitter	clinical testing	The p.T518M variant (also known as c.1553C>T), located in coding exon 12 of the APC gene, results from a C to T substitution at nucleotide position 1553. The threonine at codon 518 is replaced by methionine, an amino acid with similar 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, 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.
Invitae	RCV003650489	SCV000552767	uncertain significance	Familial adenomatous polyposis 1	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 518 of the APC protein (p.Thr518Met). This variant is present in population databases (rs371453363, gnomAD 0.006%). 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: 231917). 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	RCV000221284	SCV000681472	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 518 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 5/282234 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.
Mendelics	RCV000461223	SCV000838074	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764560	SCV000895648	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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284232	SCV001469898	uncertain significance	not provided	2019-11-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001284232	SCV001813236	uncertain significance	not provided	2023-02-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed among unaffected controls, but not among 165 colorectal cancer and/or polyposis cases (Rosenthal et al., 2018); This variant is associated with the following publications: (PMID: 18199528, 30267214)