ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3739G>A (p.Ala1247Thr) (rs148223181)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163815 SCV000214399 benign Hereditary cancer-predisposing syndrome 2015-05-14 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV001086550 SCV000259947 benign Familial adenomatous polyposis 1 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000589358 SCV000293067 likely benign not provided 2021-05-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 18199528, 24599579, 28576136, 28135145)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235835 SCV000694036 benign not specified 2019-11-08 criteria provided, single submitter clinical testing Variant summary: APC c.3739G>A (p.Ala1247Thr) 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. The variant allele was found at a frequency of 0.00015 in 282824 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.3739G>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis and colorectal cancer (Azzopard_2008, Grandval_2014, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. In addition, Grandval_2014 reports co-occurrence with another pathogenic APC variant (c.3201dup, p.Ser1068Ilefs*13), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Color Health, Inc RCV000163815 SCV000910767 benign Hereditary cancer-predisposing syndrome 2016-03-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589358 SCV001133327 benign not provided 2018-10-11 criteria provided, single submitter clinical testing

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