Submissions for variant NM_000038.6(APC):c.6907G>A (p.Gly2303Arg)

dbSNP: rs544549596

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001356898	SCV000292986	likely benign	not provided	2021-02-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327)
Invitae	RCV000546435	SCV000647680	benign	Familial adenomatous polyposis 1	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574195	SCV000667355	likely benign	Hereditary cancer-predisposing syndrome	2018-09-14	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	RCV000574195	SCV000681833	likely benign	Hereditary cancer-predisposing syndrome	2018-04-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000546435	SCV000785432	uncertain significance	Familial adenomatous polyposis 1	2017-08-07	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001356898	SCV002010863	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000574195	SCV002526831	likely benign	Hereditary cancer-predisposing syndrome	2022-02-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120043	SCV002550649	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315719	SCV004018761	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.
ITMI	RCV000120043	SCV000084176	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356898	SCV001552181	uncertain significance	not provided		no assertion criteria provided	clinical testing	The APC p.Gly2303Arg variant was identified in 1 of 1362 proband chromosomes (frequency: 0.0007) from healthy individuals (Bodian 2014). The variant was also identified in the following databases: dbSNP (ID: rs544549596) as "With Uncertain significance allele", ClinVar (1x uncertain significance, 2x likely benign), Clinvitae, and Cosmic (2X, confirmed somatic, in carcinoma of the upper aerodigestive tract). The variant was not identified in MutDB, LOVD 3.0, UMD-LSDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 85 of 245790 chromosomes (1 homozygous) 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 South Asian in 85 of 30774 chromosomes (freq: 0.003), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Gly2303 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Arginine variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. This variant is classified as a variant of uncertain significance.