ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5065A>G (p.Thr1689Ala)

gnomAD frequency: 0.00001  dbSNP: rs748577894
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000579992 SCV000681704 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-03 criteria provided, single submitter clinical testing This missense variant replaces threonine with alanine at codon 1689 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/249558 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.
Invitae RCV003537228 SCV000941816 uncertain significance Familial adenomatous polyposis 1 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1689 of the APC protein (p.Thr1689Ala). This variant is present in population databases (rs748577894, gnomAD 0.003%). 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: 489462). 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.
Ambry Genetics RCV000579992 SCV001185382 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-08 criteria provided, single submitter clinical testing The p.T1689A variant (also known as c.5065A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 5065. The threonine at codon 1689 is replaced by alanine, 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.
GeneDx RCV001558586 SCV001780569 uncertain significance not provided 2019-12-16 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this 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: 23700467)

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