Submissions for variant NM_000038.6(APC):c.7625A>G (p.Asn2542Ser)

gnomAD frequency: 0.00016  dbSNP: rs151163793

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003534362	SCV000166059	benign	Familial adenomatous polyposis 1	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000766452	SCV000292466	likely benign	not provided	2021-01-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer and leukemia (Zhang 2015, Yurgelun 2017); This variant is associated with the following publications: (PMID: 25471132, 26580448, 28135145)
Counsyl	RCV000122802	SCV000488366	uncertain significance	Familial adenomatous polyposis 1	2016-03-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766452	SCV000600157	likely benign	not provided	2020-10-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575243	SCV000667284	likely benign	Hereditary cancer-predisposing syndrome	2020-05-29	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.
Color Diagnostics, LLC DBA Color Health	RCV000575243	SCV000903019	likely benign	Hereditary cancer-predisposing syndrome	2016-03-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235882	SCV000918429	likely benign	not specified	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: APC c.7625A>G (p.Asn2542Ser) results in a conservative amino acid change located in the basic domain (IPR009232) of 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 250670 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 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.7625A>G has been reported in the literature as a VUS in settings of multigene panel testing in an individual affected with colorectal cancer (Yurgelun_2017) and as probably benign an individual affected with ALL (Zhang_2015). 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. The following publications have been ascertained in the context of this evaluation (PMID: 28135145, 26580448). Eight other 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 (uncertain significance, n=3; likely benign/benign, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000122802	SCV001136947	uncertain significance	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000575243	SCV002528259	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000122802	SCV004018762	likely benign	Familial adenomatous polyposis 1	2023-02-21	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.