Submissions for variant NM_000038.6(APC):c.5392A>G (p.Asn1798Asp)

gnomAD frequency: 0.00012  dbSNP: rs200794097

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035077	SCV000058717	likely benign	not specified	2019-05-02	criteria provided, single submitter	clinical testing	The p.Asn1798Asp variant in APC is classified as likely benign because it has been identified in 0.053% (13/24620) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org), and computational tools suggest that this variant may not impact the protein. This variant has been reported in ClinVar (Variation ID 41532) and has been observed in 1/403 individuals with atherosclerosis and in 1 South African individual with colorectal cancer (Johnston 2012, Felix 2003); however its allele frequency of 0.053% is higher than expected for a pathogenic APC variant associated with familial adenomatous polyposis, which has an estimated prevalence of 1/7000. ACMG/AMP criteria applied: BS1, BP4.
GeneDx	RCV000034417	SCV000209532	uncertain significance	not provided	2018-06-25	criteria provided, single submitter	clinical testing	This variant is denoted APC c.5392A>G at the cDNA level, p.Asn1798Asp (N1798D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAT>GAT). This variant was observed in 1/430 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). APC Asn1798Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). APC Asn1798Asp is located in the beta-catenin binding domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Asn1798Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV003315549	SCV000218647	likely benign	Familial adenomatous polyposis 1	2024-01-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000167996	SCV000488327	uncertain significance	Familial adenomatous polyposis 1	2016-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491791	SCV000579863	benign	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034417	SCV000600115	likely benign	not provided	2022-12-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491791	SCV000681736	likely benign	Hereditary cancer-predisposing syndrome	2020-07-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000167996	SCV000838133	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035077	SCV001361423	likely benign	not specified	2021-09-20	criteria provided, single submitter	clinical testing	Variant summary: APC c.5392A>G (p.Asn1798Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 280972 control chromosomes, predominantly at a frequency of 0.00053 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 7-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. The variant, c.5392A>G, has been reported in the literature in individuals affected with atherosclerosis, pediatric astrocytoma, and breast cancer (Johnston_2012, Muskens_2020, Sandoval_2021). These reports 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. Eight other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=6) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000491791	SCV002535641	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315549	SCV004018807	uncertain significance	Familial adenomatous polyposis 1	2023-02-22	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034417	SCV000043132	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.