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

Total submissions: 8

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