ClinVar Miner

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

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Total submissions: 9
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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 2019-03-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Invitae RCV000987571 SCV000259988 likely benign Familial adenomatous polyposis 1 2019-12-31 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
Color RCV000115091 SCV000910826 benign Hereditary cancer-predisposing syndrome 2016-03-22 criteria provided, single submitter clinical testing
Mendelics RCV000987571 SCV001136910 benign Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000417367 SCV001339030 benign not specified 2020-03-09 criteria provided, single submitter clinical testing Variant summary: APC c.4336G>A (p.Ala1446Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This is further supported by a functional study, (Azzopardi et al_2008), that demonstrated that the effect of this variant on suppression of beta-catenin regulated transcription (CRT) was identical to the wild-type in well controlled experimental system. The variant allele was found at a frequency of 0.00017 in 284482 control chromosomes, predominantly at a frequency of 0.0016 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 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 African or African-American origin. c.4336G>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (Azzopardi_2008, Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At least one co-occurrence with another pathogenic variant has been reported internally (PMS2 c.2186_2187delTC, p.Leu729GlnfsX6), providing supporting evidence for a benign role. Five ClinVar submitters (evaluation after 2014) cite the variant as benign (2x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as benign.
CSER _CC_NCGL, University of Washington 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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