Submissions for variant NM_000038.6(APC):c.6662T>C (p.Met2221Thr)

gnomAD frequency: 0.00003  dbSNP: rs730881255

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766445	SCV000209537	uncertain significance	not provided	2020-06-16	criteria provided, single submitter	clinical testing	Has not been previously published as a pathogenic or benign germline variant to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30148152, 32390703)
Ambry Genetics	RCV000159565	SCV000215472	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-01	criteria provided, single submitter	clinical testing	The p.M2221T variant (also known as c.6662T>C), located in coding exon 15 of the APC gene, results from a T to C substitution at nucleotide position 6662. The methionine at codon 2221 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved through mammals but not in all 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000211928	SCV000600134	uncertain significance	not specified	2017-06-07	criteria provided, single submitter	clinical testing
Invitae	RCV003534412	SCV000936885	uncertain significance	Familial adenomatous polyposis 1	2023-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2221 of the APC protein (p.Met2221Thr). This variant is present in population databases (rs730881255, gnomAD 0.005%). 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: 181813). 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. 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	RCV000159565	SCV001353123	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-01	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 2221 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 been reported in an individual affected with Peutz-Jeghers syndrome (PMID: 30148152). This variant has been identified in 2/281352 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.
Sema4, Sema4	RCV000159565	SCV002528853	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-12	criteria provided, single submitter	curation
Baylor Genetics	RCV002516414	SCV004200165	uncertain significance	Familial adenomatous polyposis 1	2023-09-27	criteria provided, single submitter	clinical testing