ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3479C>A (p.Thr1160Lys) (rs201004111)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130655 SCV000185540 likely benign Hereditary cancer-predisposing syndrome 2018-11-29 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);in silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000034385 SCV000209515 uncertain significance not provided 2018-11-21 criteria provided, single submitter clinical testing This variant is denoted APC c.3479C>A at the cDNA level, p.Thr1160Lys (T1160K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). This variant has been observed in at least one individual with colorectal adenomas and one with colorectal cancer (Azzopardi 2008, Raskin 2017). APC Thr1160Lys was observed at an allele frequency of 0.02% (28/126,390) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the beta-catenin 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 Thr1160Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204291 SCV000259359 likely benign Familial adenomatous polyposis 1 2019-12-27 criteria provided, single submitter clinical testing
Counsyl RCV000204291 SCV000487797 uncertain significance Familial adenomatous polyposis 1 2015-11-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000235094 SCV000538297 uncertain significance not specified 2017-01-24 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: This variant is classified as DM in HGMD - it has been seen in one patient with colorectal adenoma and one unaffected patient. It has been classified with 1 star as VUS by 4 sumitters (GeneDx, Invitae, CSER_CC_NCGL, Biesecker lab) and Likely benign by 1 (Ambry). MaxMAF is 0.02% in ExAC (high for disease prevalence).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034385 SCV000600083 uncertain significance not provided 2019-01-17 criteria provided, single submitter clinical testing
Color RCV000130655 SCV000681610 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000235094 SCV000916470 uncertain significance not specified 2018-04-16 criteria provided, single submitter clinical testing Variant summary: APC c.3479C>A (p.Thr1160Lys) results in a non-conservative amino acid change located in one of the 15 residue repeat domains (IPR009240) that is involved in beta-catenin binding (Azzopardi 2008). Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 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. The variant, c.3479C>A, has been reported in the literature in individuals affected with colorectal adenomas (Azzopardi 2008) and in a family with colorectal cancer without polyps (Raskin 2017). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and 6 of them classified the variant as a VUS, while 1 laboratory classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics RCV000204291 SCV001136903 benign Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034385 SCV000043123 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington RCV000148371 SCV000190064 uncertain significance Colorectal adenoma 2014-06-01 no assertion criteria provided research

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