Submissions for variant NM_000038.6(APC):c.8389A>G (p.Ser2797Gly)

gnomAD frequency: 0.00007  dbSNP: rs147287751

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129949	SCV000184772	likely benign	Hereditary cancer-predisposing syndrome	2018-11-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198030	SCV000254049	likely benign	Familial adenomatous polyposis 1	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000656753	SCV000292468	uncertain significance	not provided	2023-06-09	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, colon polyp(s), and/or breast cancer (Tung et al., 2015; Jelsig et al., 2016; Dominguez-Valentin et al., 2017; Yurgelun et al., 2017; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 25186627, 28608266, 28135145, 16454848, 26580448, 27146957, 30122538, 35264596, 18199528)
Illumina Laboratory Services, Illumina	RCV000283075	SCV000452057	uncertain significance	APC-Associated Polyposis Disorders	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000198030	SCV000488295	uncertain significance	Familial adenomatous polyposis 1	2016-02-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656753	SCV000600167	uncertain significance	not provided	2019-04-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515282	SCV000611342	uncertain significance	Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma	2017-05-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000656753	SCV000805481	uncertain significance	not provided	2017-06-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000198030	SCV000838162	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129949	SCV000902847	likely benign	Hereditary cancer-predisposing syndrome	2016-11-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267871	SCV002550671	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267871	SCV003934296	likely benign	not specified	2023-05-31	criteria provided, single submitter	clinical testing	Variant summary: APC c.8389A>G (p.Ser2797Gly) results in a non-conservative amino acid change located in the EB-1 binding 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 9.6e-05 in 239728 control chromosomes. The observed variant frequency is approximately 1.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), suggesting that the variant is benign, however, this frequency was found almost exclusively in the non-Finnish European population. c.8389A>G has been reported in the literature as a VUS in individuals affected with colorectal, breast, colon, and lung cancers (examples: Tung_2015, Yurgelun_2017, Dominguez-Valentin_2018, Beaubier_2019, Svensson_2022), or without evidence of causality in prostate or other cancers (examples: Mateo_2020, 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(s) have been reported (CHEK2 c.319+2T>A, Dominguez-Valentin_2018), providing supporting evidence for a benign role. 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: 31570899, 28608266, 35264596, 31874108, 35430768, 25186627, 28135145, 26580448). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as uncertain significance (n=8) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Myriad Genetics, Inc.	RCV000198030	SCV004018764	uncertain significance	Familial adenomatous polyposis 1	2023-02-21	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.
Clinical Genetics, Academic Medical Center	RCV000656753	SCV001918221	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656753	SCV001954650	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000656753	SCV001979842	likely benign	not provided		no assertion criteria provided	clinical testing