ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7541C>G (p.Thr2514Ser)

gnomAD frequency: 0.00001  dbSNP: rs747833393
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564293 SCV000667253 likely benign Hereditary cancer-predisposing syndrome 2021-12-13 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health RCV000564293 SCV000687130 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-03 criteria provided, single submitter clinical testing This missense variant replaces threonine with serine at codon 2514 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 not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 2/251096 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 RCV003537098 SCV000768174 uncertain significance Familial adenomatous polyposis 1 2024-01-28 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 2514 of the APC protein (p.Thr2514Ser). This variant is present in population databases (rs747833393, gnomAD 0.002%). 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: 482240). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985320 SCV001133369 uncertain significance not provided 2019-08-27 criteria provided, single submitter clinical testing
GeneDx RCV000985320 SCV001786192 uncertain significance not provided 2019-03-06 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); 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
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV002526839 SCV004015280 uncertain significance Familial adenomatous polyposis 1 2023-07-07 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 2514 of the APC protein (p.Thr2514Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs747833393, ExAC 0.001%). This variant has not been reported in the literature in individuals with APC-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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