Submissions for variant NM_000038.6(APC):c.7472T>C (p.Met2491Thr)

gnomAD frequency: 0.00005  dbSNP: rs369075403

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164068	SCV000214678	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	The p.M2491T variant (also known as c.7472T>C), located in coding exon 15 of the APC gene, results from a T to C substitution at nucleotide position 7472. The methionine at codon 2491 is replaced by threonine, 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.
Invitae	RCV000226252	SCV000282823	uncertain significance	Familial adenomatous polyposis 1	2024-01-13	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 2491 of the APC protein (p.Met2491Thr). This variant is present in population databases (rs369075403, 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: 184756). 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.
GeneDx	RCV000590327	SCV000566115	uncertain significance	not provided	2022-12-01	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27150160)
Color Diagnostics, LLC DBA Color Health	RCV000164068	SCV000681869	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-06	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 2491 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 gynecological cancer (PMID: 27150160) and in an individual with colorectal polyposis (Jones 2008, dissertation, Cardiff University). This variant has been identified in 4/282694 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590327	SCV000694117	uncertain significance	not provided	2016-03-25	criteria provided, single submitter	clinical testing	Variant summary: The APC c.7472T>C variant affects a conserved nucleotide, resulting in an amino acid change from Met to Thr. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index); however, it has not been evaluated for functional impact by in vivo/vitro studies. This variant was found in 1/121366 control chromosomes at a frequency of 0.0000082, which does not significantly exceed maximal expected frequency of a pathogenic APC allele (0.0000602). In addition, one clinical laboratory classified this variant as a VUS. The variant of interest has been reported in one colorectal polyposis patient to co-occur with an unspecified APC truncating variant (Jones_Thesis_2008), suggesting that this APC variant may be benign. However, in the absence of functional studies, and detailed clinical and genotype information, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl	RCV000226252	SCV000784802	uncertain significance	Familial adenomatous polyposis 1	2016-12-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164068	SCV002530173	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-20	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000226252	SCV004017903	uncertain significance	Familial adenomatous polyposis 1	2023-02-16	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000226252	SCV004199432	uncertain significance	Familial adenomatous polyposis 1	2023-10-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590327	SCV004220564	uncertain significance	not provided	2023-01-13	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000023 (3/129046 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with an unspecified gynecological cancer (PMID: 27150160 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.