ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5009C>T (p.Ala1670Val) (rs202228932)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122783 SCV000166040 uncertain significance Familial adenomatous polyposis 1 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1670 of the APC protein (p.Ala1670Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs202228932, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with familial adenomatous polyposis (PMID: 27705013), and an individual with a clinical history suggestive of Lynch or polyposis syndrome (PMID: 28502729). ClinVar contains an entry for this variant (Variation ID: 135705). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000128987 SCV000172877 likely benign Hereditary cancer-predisposing syndrome 2017-12-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
GeneDx RCV000586353 SCV000292460 uncertain significance not provided 2018-02-20 criteria provided, single submitter clinical testing This variant is denoted APC c.5009C>T at the cDNA level, p.Ala1670Val (A1670V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). This variant has been identified in at least one individual with a personal history of colon polyps and in one individual with early-onset colorectal cancer (Marabelli 2016, DeRycke 2017). It has also been observed in individuals undergoing panel testing for hereditary breast and ovarian cancer or hereditary colon cancer (Lincoln 2015, Rey 2017). APC Ala1670Val was observed at an allele frequency of 0.04% (41/125,686) in individuals of European (Non-Finnish) ancestry in large population cohorts (Lek 2016). This variant is located in the beta-catenin binding 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 Ala1670Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000236885 SCV000591183 uncertain significance not specified 2014-10-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000236885 SCV000694066 likely benign not specified 2019-02-22 criteria provided, single submitter clinical testing Variant summary: APC c.5009C>T (p.Ala1670Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 281640 control chromosomes, predominantly at a frequency of 0.00033 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 4.6 fold of 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. This variant has been reported in individuals affected with-, or a clinical history suggestive of, adenomatous polyposis or early-onset colorectal cancer (Marabelli 2016, DeRycke 2017, Rey 2017, Henn 2019), and also found in individuals affected with- or undergoing testing for other tumor phenotypes (Lincoln 2015, Zhang 2015); however without strong evidence for causality (i.e. no co-segregation data were provided). These reports thus 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 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000122783 SCV000784749 uncertain significance Familial adenomatous polyposis 1 2017-11-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000586353 SCV000805418 uncertain significance not provided 2017-11-20 criteria provided, single submitter clinical testing
Mendelics RCV000122783 SCV000838125 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000128987 SCV000910625 likely benign Hereditary cancer-predisposing syndrome 2016-06-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586353 SCV001133340 likely benign not provided 2019-02-18 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586353 SCV001154470 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000236885 SCV000691756 uncertain significance not specified no assertion criteria provided clinical testing

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