ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2942C>G (p.Pro981Arg) (rs587779784)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115075 SCV000148984 uncertain significance not provided 2018-10-09 criteria provided, single submitter clinical testing This variant is denoted APC c.2942C>G at the cDNA level, p.Pro981Arg (P981R) at the protein level, and results in the change of a Proline to an Arginine (CCC>CGC). This variant was observed in two individuals with colorectal adenomas who were classified as non-FAP, non-MAP patients (Azzopardi 2008). APC Pro981Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether APC Pro981Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
CSER _CC_NCGL, University of Washington RCV000211505 SCV000212180 uncertain significance Familial adenomatous polyposis 1 2015-03-11 criteria provided, single submitter research
Invitae RCV000211505 SCV000647284 uncertain significance Familial adenomatous polyposis 1 2018-03-25 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 981 of the APC protein (p.Pro981Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs587779784, ExAC 0.002%). This variant has been reported in individuals affected with colorectal adenomas (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 127282). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; 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.
Color RCV000581785 SCV000686918 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780838 SCV000918443 uncertain significance not specified 2018-06-08 criteria provided, single submitter clinical testing Variant summary: APC c.2942C>G (p.Pro981Arg) 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 1.2e-05 in 247994 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2942C>G has been reported in the literature in individuals affected with colorectal adenomas and CRC. These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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