Submissions for variant NM_000038.6(APC):c.6136G>A (p.Ala2046Thr)

gnomAD frequency: 0.00001  dbSNP: rs770406711

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164449	SCV000215091	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-15	criteria provided, single submitter	clinical testing	The p.A2046T variant (also known as c.6136G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 6136. The alanine at codon 2046 is replaced by threonine, an amino acid with similar properties. One study detected this alteration in 1/274 familial colorectal cancer patients who underwent multigene panel testing (Hansen MF et al. Clin. Genet., 2017 Oct;92:405-414). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000411350	SCV000488440	uncertain significance	Familial adenomatous polyposis 1	2016-03-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411350	SCV000552458	uncertain significance	Familial adenomatous polyposis 1	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2046 of the APC protein (p.Ala2046Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with colorectal cancer (PMID: 28195393). ClinVar contains an entry for this variant (Variation ID: 185089). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
GeneDx	RCV000759436	SCV000564578	uncertain significance	not provided	2019-06-28	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28195393, 25545608)
Color Diagnostics, LLC DBA Color Health	RCV000164449	SCV000681785	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 2046 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28195393). This variant has been identified in 2/250780 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	RCV000759436	SCV000888755	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000411350	SCV001136929	uncertain significance	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411350	SCV004018002	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	RCV000411350	SCV004203401	uncertain significance	Familial adenomatous polyposis 1	2023-07-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995342	SCV004838150	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 2046 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28195393). This variant has been identified in 2/250780 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.
PreventionGenetics, part of Exact Sciences	RCV004739520	SCV005357756	uncertain significance	APC-related disorder	2024-04-09	no assertion criteria provided	clinical testing	The APC c.6136G>A variant is predicted to result in the amino acid substitution p.Ala2046Thr. This variant has been reported in an individual with familial colorectal cancer (Hansen et al. 2017. PubMed ID: 28195393). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185089/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.