ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2993G>T (p.Gly998Val)

gnomAD frequency: 0.00001  dbSNP: rs759579036
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216134 SCV000277964 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-28 criteria provided, single submitter clinical testing The p.G998V variant (also known as c.2993G>T), located in coding exon 15 of the APC gene, results from a G to T substitution at nucleotide position 2993. The glycine at codon 998 is replaced by valine, an amino acid with dissimilar properties. This variant has been detected in a patient with a history of a Lynch syndrome-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149(3):604-13.e20). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000761125 SCV000891041 uncertain significance Familial adenomatous polyposis 1 2021-08-03 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000216134 SCV000909257 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-21 criteria provided, single submitter clinical testing This missense variant replaces glycine with valine at codon 998 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 been reported in an individual suspected of having Lynch syndrome (PMID: 25980754). This variant has been identified in 3/251292 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 RCV000761125 SCV002237424 uncertain significance Familial adenomatous polyposis 1 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 998 of the APC protein (p.Gly998Val). This variant is present in population databases (rs759579036, gnomAD 0.009%). This missense change has been observed in individual(s) with Lynch syndrome-related cancers (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 233564). 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.
GeneDx RCV003325472 SCV004031676 uncertain significance not provided 2023-08-30 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one individual who had a history of Lynch syndrome-associated cancer and/or polyps (Yurgelun et al., 2015); This variant is associated with the following publications: (PMID: 25980754)
Baylor Genetics RCV000761125 SCV004198292 uncertain significance Familial adenomatous polyposis 1 2023-09-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003325472 SCV004222390 uncertain significance not provided 2022-10-07 criteria provided, single submitter clinical testing To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000087 (3/34588 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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