ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2847G>T (p.Met949Ile) (rs147394539)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159544 SCV000209508 likely benign not specified 2017-12-07 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.
Invitae RCV000168133 SCV000218792 benign Familial adenomatous polyposis 1 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000168133 SCV000488505 uncertain significance Familial adenomatous polyposis 1 2016-04-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567920 SCV000667228 likely benign Hereditary cancer-predisposing syndrome 2018-09-17 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Mendelics RCV000168133 SCV000838095 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000567920 SCV000902832 likely benign Hereditary cancer-predisposing syndrome 2016-05-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000159544 SCV000918467 likely benign not specified 2019-12-31 criteria provided, single submitter clinical testing Variant summary: APC c.2847G>T (p.Met949Ile) results in a 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 4.8e-05 in 250790 control chromosomes, predominantly at a frequency of 0.00068 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 9.5 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.2847G>T has been reported in the literature in at-least two individuals, one stated as affected with non-familial adenomatous polyposis and non MUTYH-associated polyposis (Azzopard_2008) and another with Ependymoma in a sequencing study of 1120 young cancer patients (Zhang_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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation reporting conflicting assessments (benign, n=1; likely benign, n=3; VUS, n=2). Based on the evidence outlined above, the variant was re-classified as likely benign.
CSER _CC_NCGL, University of Washington RCV000148363 SCV000190055 uncertain significance Colorectal adenoma 2014-06-01 no assertion criteria provided research

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