ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6473C>G (p.Pro2158Arg) (rs587779804)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587692 SCV000149021 uncertain significance not provided 2018-12-19 criteria provided, single submitter clinical testing This variant is denoted APC c.6473C>G at the cDNA level, p.Pro2158Arg (P2158R) at the protein level, and results in the change of a Proline to an Arginine (CCC>CGC). This variant has been reported in an individual with colorectal adenomas, an individual with colorectal cancer, and in an individual with breast cancer (Azzopardi 2008, Tung 2015, Pearlman 2017). APC Pro2158Arg was observed at an allele frequency of 0.01% (3/23,958) in individuals of African ancestry 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Pro2158Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000122792 SCV000166049 uncertain significance Familial adenomatous polyposis 1 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 2158 of the APC protein (p.Pro2158Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is present in population databases (rs587779804, ExAC 0.03%). This variant has been reported in an individual with colorectal adenomas (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 127313). 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: "Tolerated"; 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.
Ambry Genetics RCV000115112 SCV000186636 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000235096 SCV000538304 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband; Clinvar: 4 vus
Color RCV000115112 SCV000681800 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000235096 SCV000694095 uncertain significance not specified 2019-01-07 criteria provided, single submitter clinical testing Variant summary: The variant, APC c.6473C>G (p.Pro2158Arg) 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 5e-05 in 278626 control chromosomes (gnomAD and Azzopardi_2008). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.6473C>G has been reported in the literature in individuals affected with colorectal cancer, familial adenomatous polyposis, and breast cancer (Azzopardi_2008, Pearlman_2016, Zhang_2015). However, these reports 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. Six 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.
GeneKor MSA RCV000115112 SCV000821820 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Pathway Genomics RCV000122792 SCV000189871 uncertain significance Familial adenomatous polyposis 1 2014-07-24 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.