Submissions for variant NM_000038.6(APC):c.777G>T (p.Arg259=)

dbSNP: rs147704593

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV004019702	SCV000166061	benign	Familial adenomatous polyposis 1	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000211894	SCV000167021	benign	not specified	2014-02-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000123678	SCV000213055	likely benign	Hereditary cancer-predisposing syndrome	2014-09-25	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.
Color Diagnostics, LLC DBA Color Health	RCV000123678	SCV000537449	likely benign	Hereditary cancer-predisposing syndrome	2016-06-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759445	SCV000888768	benign	not provided	2022-11-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211894	SCV000916471	benign	not specified	2018-04-16	criteria provided, single submitter	clinical testing	Variant summary: APC c.777G>T alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 77 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 Ashkenazi Jewish origin. The variant, c.777G>T, has been reported in the literature in one individual affected with Familial Adenomatous Polyposis (Kerr 2013). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV001151508	SCV001312639	uncertain significance	APC-Associated Polyposis Disorders	2017-05-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CeGaT Center for Human Genetics Tuebingen	RCV000759445	SCV001335133	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	APC: BP4, BP7
Sema4, Sema4	RCV000123678	SCV002530832	benign	Hereditary cancer-predisposing syndrome	2020-07-02	criteria provided, single submitter	curation
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000123678	SCV002819152	likely benign	Hereditary cancer-predisposing syndrome	2022-12-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997388	SCV004837324	likely benign	Classic or attenuated familial adenomatous polyposis	2023-12-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004019702	SCV004931026	benign	Familial adenomatous polyposis 1	2024-02-27	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353450	SCV000591052	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Arg259= variant was identified in 1 of 3182 proband chromosomes (frequency: 0.0003) from individuals or families with FAP (Kerr 2013). The variant was also identified in dbSNP (ID: rs147704593) as With other allele, ClinVar (classified as benign by Invitae, GeneDx; classified as likely benign by Ambry Genetics, Color Genomics and two clinical laboratories), GeneInsight-COGR, and LOVD 3.0 databases. The variant was not identified in UMD-LSDB database or Zhejiang Colon Cancer Database. The variant was identified in control databases in 65 of 245844 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 4 of 5476 chromosomes (freq: 0.000731), Latino in 1 of 33516 chromosomes (freq: 0.00003), European Non-Finnish in 6 of 111470 chromosomes (freq: 0.000054), Ashkenazi Jewish in 54 of 9836 chromosomes (freq: 0.00549), while the variant was not observed in the African, East Asian, European Finnish, and South Asian populations. The p.Arg259= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000211894	SCV000691709	likely benign	not specified		no assertion criteria provided	clinical testing