ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5528C>T (p.Pro1843Leu) (rs368080169)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000679068 SCV000149013 uncertain significance not provided 2018-06-27 criteria provided, single submitter clinical testing This variant is denoted APC c.5528C>T at the cDNA level, p.Pro1843Leu (P1843L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). This variant has been reported in one individual with colon cancer and another individual with a Lynch syndrome-associated cancer and/or colon polyps (Hadjisavvas 2006, Yurgelun 2015). APC Pro1843Leu was observed at an allele frequency of 0.02% (20/111,308) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the 20-aa repeat B-catenin down-regulating domain and 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 Pro1843Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000148372 SCV000254025 uncertain significance Familial adenomatous polyposis 1 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1843 of the APC protein (p.Pro1843Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs368080169, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with colorectal cancer and polyposis (PMID: 16650078), and in an individual with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127306). 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: "Probably 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.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000202997 SCV000257787 uncertain significance Familial multiple polyposis syndrome 2015-02-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000115104 SCV000538302 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: Only reported in 1 or 2 probands; ClinVar: 4 VUS
Ambry Genetics RCV000572635 SCV000667335 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000572635 SCV000681748 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000679068 SCV000702013 uncertain significance not provided 2016-10-24 criteria provided, single submitter clinical testing
Counsyl RCV000148372 SCV000785043 uncertain significance Familial adenomatous polyposis 1 2017-03-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679068 SCV000805436 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing
GeneKor MSA RCV000572635 SCV000821817 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000115104 SCV000916458 uncertain significance not specified 2019-05-23 criteria provided, single submitter clinical testing Variant summary: APC c.5528C>T (p.Pro1843Leu) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein repeat region of the encoded protein sequence. 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 8.4e-05 in 251106 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.5528C>T has been reported in the literature in individuals affected with Familial Adenomatous Polyposis, Colorectal cancer, Lynch syndrome and HBOC (Hadjisavvas_2006, Yurgelun_2015, Lupini_2015, Zidan_2017). 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. Ten ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
CSER _CC_NCGL, University of Washington RCV000148372 SCV000190066 uncertain significance Familial adenomatous polyposis 1 2014-06-01 no assertion criteria provided research

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