Submissions for variant NM_000038.6(APC):c.3650A>C (p.Asn1217Thr)

gnomAD frequency: 0.00038  dbSNP: rs138933660

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131570	SCV000186574	likely benign	Hereditary cancer-predisposing syndrome	2019-03-06	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.
Invitae	RCV003743572	SCV000254010	benign	Familial adenomatous polyposis 1	2024-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000587732	SCV000292457	likely benign	not provided	2020-11-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19506109, 24728327, 21567896, 27978560, 28873162)
Counsyl	RCV000199645	SCV000488023	uncertain significance	Familial adenomatous polyposis 1	2015-12-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120014	SCV000694035	likely benign	not specified	2020-09-28	criteria provided, single submitter	clinical testing	Variant summary: APC c.3650A>C (p.Asn1217Thr) 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 0.0002 in 251760 control chromosomes, predominantly at a frequency of 0.0026 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 36 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.3650A>C has been reported in the literature in an individual affected with cancer of cecum and also in breast cancer high-risk families. (Pearlman_2016, Bonache_2018) . However, this report does 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 other ClinVar submitters (evaluation after 2014) cite the variant as likely bening/benign (n=4) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000587732	SCV000805401	likely benign	not provided	2019-10-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131570	SCV000911206	benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131570	SCV002533869	likely benign	Hereditary cancer-predisposing syndrome	2021-03-02	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003315713	SCV004018799	likely benign	Familial adenomatous polyposis 1	2023-02-22	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	RCV000120014	SCV004025055	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587732	SCV004222572	benign	not provided	2022-10-11	criteria provided, single submitter	clinical testing
ITMI	RCV000120014	SCV000084144	not provided	not specified	2013-09-19	no assertion provided	reference population