ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4336G>A (p.Ala1446Thr) (rs146572883)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000417367 SCV000149000 likely benign not specified 2018-01-03 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115091 SCV000172883 likely benign Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Intact protein function observed in appropriate functional assay(s)
Invitae RCV000203926 SCV000259988 likely benign Familial adenomatous polyposis 1 2017-12-27 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000417367 SCV000591168 likely benign not specified 2013-01-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588958 SCV000694050 likely benign not provided 2017-07-21 criteria provided, single submitter clinical testing Variant summary: The APC c.4336G>A (p.Ala1446Thr) variant involves the alteration of a conserved nucleotide resulting in a non-conservative amino acid change located in the beta-catenin down regulating domain (codons 1262-2033) of the APC protein. 3/4 in silico tools (SNPsandGO not captured due to low reliability index)predict a benign outcome. This is further supported by a functional study, (Azzopardi et al_2008), that demonstrated that the effect of this variant on supression of beta-catenin regulated transcription (CRT) was identical to the wild-type in well controled experimental system. This variant was found in 48/278826 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.001666 (40/24012). This frequency is about 23 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Multiple publications have cited the variant of interest in affected individuals including one publication indicating the variant is likely benign (Zhang_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
Color RCV000115091 SCV000910826 benign Hereditary cancer-predisposing syndrome 2016-03-22 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148364 SCV000190056 uncertain significance Colorectal adenoma 2014-06-01 no assertion criteria provided research
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000417367 SCV000691749 uncertain significance not specified no assertion criteria provided clinical testing

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