Submissions for variant NM_000038.6(APC):c.4478C>T (p.Thr1493Met)

gnomAD frequency: 0.00006  dbSNP: rs374892194

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130087	SCV000184915	benign	Hereditary cancer-predisposing syndrome	2021-03-17	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000590777	SCV000209526	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individual(s) with colorectal cancer, but also in unaffected controls (Azzopardi et al., 2008; DeRycke et al., 2017); This variant is associated with the following publications: (PMID: 26486734, 18199528, 28944238, 35709138)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228695	SCV000282755	uncertain significance	Familial adenomatous polyposis 1	2024-01-31	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 1493 of the APC protein (p.Thr1493Met). This variant is present in population databases (rs374892194, gnomAD 0.01%). 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: 141521). 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.
Counsyl	RCV000228695	SCV000488216	uncertain significance	Familial adenomatous polyposis 1	2016-01-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590777	SCV000694054	uncertain significance	not provided	2017-06-16	criteria provided, single submitter	clinical testing	Variant summary: The APC c.4478C>T (p.Thr1493Met) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant. This variant was found in 5/123012 control chromosomes at a frequency of 0.0000406, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). The variant was detected in one breast tumor sample and in a control individual in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence becomes available.
Eurofins Ntd Llc (ga)	RCV000590777	SCV000859960	uncertain significance	not provided	2018-03-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130087	SCV000905985	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1493 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 a healthy control individual (PMID 18199528). This variant has been identified in 8/281844 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	RCV000130087	SCV002534294	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-31	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130087	SCV004014962	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000228695	SCV004198270	uncertain significance	Familial adenomatous polyposis 1	2023-09-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997547	SCV004837938	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 1493 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 a healthy control individual (PMID 18199528) and in a tumor sample from an individual affected with breast cancer (PMID: 26486734). This variant has been identified in 8/281844 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.