ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs770406711
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Total submissions: 9
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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, the in silico prediction for this alteration is inconclusive. 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
Invitae RCV000411350 SCV000552458 uncertain significance Familial adenomatous polyposis 1 2024-01-07 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). 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) has been performed at Invitae 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. RCV002228719 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

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