ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1478A>G (p.Tyr493Cys)

gnomAD frequency: 0.00001  dbSNP: rs770649674
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000580474 SCV000681467 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-26 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 493 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 not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 1/251250 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 RCV003537216 SCV000831609 uncertain significance Familial adenomatous polyposis 1 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 493 of the APC protein (p.Tyr493Cys). This variant is present in population databases (rs770649674, gnomAD 0.007%). 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: 489415). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001553562 SCV001774455 uncertain significance not specified 2021-08-01 criteria provided, single submitter clinical testing Variant summary: APC c.1478A>G (p.Tyr493Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251250 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1478A>G in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics RCV000580474 SCV002700705 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-29 criteria provided, single submitter clinical testing The p.Y493C variant (also known as c.1478A>G), located in coding exon 11 of the APC gene, results from an A to G substitution at nucleotide position 1478. The tyrosine at codon 493 is replaced by cysteine, an amino acid with highly dissimilar properties. 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.
Baylor Genetics RCV002529056 SCV004205281 uncertain significance Familial adenomatous polyposis 1 2023-06-20 criteria provided, single submitter clinical testing

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