ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5996C>G (p.Pro1999Arg)

dbSNP: rs1554087137
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000584103 SCV000687057 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-07 criteria provided, single submitter clinical testing This missense variant replaces proline with arginine at codon 1999 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 hereditary cancer in the literature. This variant has not been identified 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 RCV002529161 SCV002222123 uncertain significance Familial adenomatous polyposis 1 2021-09-02 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 1999 of the APC protein (p.Pro1999Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). 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: 490325). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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 RCV000584103 SCV002656113 uncertain significance Hereditary cancer-predisposing syndrome 2022-06-20 criteria provided, single submitter clinical testing The p.P1999R variant (also known as c.5996C>G), located in coding exon 15 of the APC gene, results from a C to G substitution at nucleotide position 5996. The proline at codon 1999 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. 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.

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