ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7786T>G (p.Ser2596Ala) (rs138137162)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131566 SCV000186570 likely benign Hereditary cancer-predisposing syndrome 2018-01-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),In silico models in agreement (benign)
Invitae RCV000229880 SCV000282830 uncertain significance Familial adenomatous polyposis 1 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces serine with alanine at codon 2596 of the APC protein (p.Ser2596Ala). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and alanine. This variant is present in population databases (rs138137162, ExAC 0.009%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 142442). 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.
Counsyl RCV000229880 SCV000489526 uncertain significance Familial adenomatous polyposis 1 2016-10-19 criteria provided, single submitter clinical testing
GeneDx RCV000656752 SCV000564585 uncertain significance not provided 2018-11-27 criteria provided, single submitter clinical testing This variant is denoted APC c.7786T>G at the cDNA level, p.Ser2596Ala (S2596A) at the protein level, and results in the change of a Serine to an Alanine (TCA>GCA). This variant has been identified in an individual with at least 10 colorectal adenomas and in a woman with endometrial cancer undergoing hereditary cancer panel testing (Out 2015, Ring 2016). APC Ser2596Ala was not observed a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the EB1 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 Ser2596Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478677 SCV000600160 uncertain significance not specified 2017-07-11 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000478677 SCV000602506 uncertain significance not specified 2016-09-26 criteria provided, single submitter clinical testing
Mendelics RCV000229880 SCV000838156 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000131566 SCV000902902 likely benign Hereditary cancer-predisposing syndrome 2016-03-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000478677 SCV000918472 likely benign not specified 2018-11-30 criteria provided, single submitter clinical testing Variant summary: APC c.7786T>G (p.Ser2596Ala) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 276400 control chromosomes, predominantly at a frequency of 8.7e-05 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 1.22 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. c.7786T>G has been reported in the literature in individuals affected with colorectal polyps, ovarian and endometrial cancer (Out_2015, Ring_2016, Schwarz_2015). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, six classify as VUS and one classifies as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
True Health Diagnostics RCV000131566 SCV000886661 likely benign Hereditary cancer-predisposing syndrome 2018-09-11 no assertion criteria provided clinical testing

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