ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5801C>T (p.Pro1934Leu) (rs587780600)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122787 SCV000166044 uncertain significance Familial adenomatous polyposis 1 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1934 of the APC protein (p.Pro1934Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs587780600, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with multiple colorectal adenomas (PMID: 18199528) and breast cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 135709). 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: "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.
GeneDx RCV000656747 SCV000209534 uncertain significance not provided 2018-08-02 criteria provided, single submitter clinical testing This variant is denoted APC c.5801C>T at the cDNA level, p.Pro1934Leu (P1934L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). This variant, also published as APC Pro1619Leu using alternate nomenclature, was reported in an individual with adenomatous colorectal polyps and in another individual with colorectal cancer (Azzopardi 2008, Pritchard 2018). APC Pro1934Leu was observed at an allele frequency of 0.04% (14/34,374) in individuals of Latino ancestry in large population cohorts (Lek 2016). APC Pro1934Leu is located within the 20-amino acid repeat beta-catenin down-regulating domain as well as the SAMP repeats/axin binding domain (Azzopardi 2008). 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 Pro1934Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000159562 SCV000213581 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000210900 SCV000264591 uncertain significance Familial multiple polyposis syndrome 2015-12-01 criteria provided, single submitter research
University of Washington Department of Laboratory Medicine,University of Washington RCV000210078 SCV000266143 uncertain significance Colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211923 SCV000538300 uncertain significance not specified 2016-03-31 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: 1 report in probands; ExAC: 6/11510 Latino; ClinVar: 3 VUS
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000211923 SCV000600120 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Color RCV000159562 SCV000681763 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing
Mendelics RCV000122787 SCV000838137 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764567 SCV000895655 uncertain significance Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000211923 SCV000918453 likely benign not specified 2018-10-19 criteria provided, single submitter clinical testing Variant summary: APC c.5801C>T (p.Pro1934Leu) results in a non-conservative amino acid change located in one of the 20-amino acid beta-catenin down-regulating repeats domain (20AAR) (Azzopardi 2008). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 275668 control chromosomes, predominantly at a frequency of 0.00041 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 6-fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), suggesting that the variant might be a benign polymorphism. The variant, c.5801C>T, has been reported in the literature in one individual affected with multiple colorectal adenomas (Azzopardi 2008), and in other patients with various tumor phenotypes (Zhang 2015, Shirts 2015, Pritchard 2018). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At least one publication reported experimental evidence evaluating an impact on protein function and demonstrated no damaging effect for this variant (Azzopardi 2008). Nine 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 likely benign.

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