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

gnomAD frequency: 0.00039  dbSNP: rs147394539

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704072	SCV000209508	likely benign	not provided	2020-11-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25637381, 21859464, 24055113, 18199528, 26991699)
Invitae	RCV003534394	SCV000218792	benign	Familial adenomatous polyposis 1	2024-01-31	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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Mendelics	RCV000168133	SCV000838095	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000567920	SCV000902832	likely benign	Hereditary cancer-predisposing syndrome	2016-05-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000159544	SCV000918467	benign	not specified	2021-12-13	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. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.8548_8551delGAAG, p.Glu2850fs), providing supporting evidence for a benign role. 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. Multiple laboratories reported the variant with conflicting assessments (benign, n=1; likely benign, n=3; VUS, n=2). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000567920	SCV002529956	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-16	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000168133	SCV004018521	likely benign	Familial adenomatous polyposis 1	2023-02-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000159544	SCV004025047	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003917461	SCV004731186	likely benign	APC-related condition	2024-02-04	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
CSER _CC_NCGL, University of Washington	RCV000148363	SCV000190055	uncertain significance	Colorectal adenoma	2014-06-01	no assertion criteria provided	research