Submissions for variant NM_000038.6(APC):c.1557A>G (p.Leu519=)

gnomAD frequency: 0.00003  dbSNP: rs765537673

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162809	SCV000213290	likely benign	Hereditary cancer-predisposing syndrome	2018-05-30	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	RCV000162809	SCV000681474	likely benign	Hereditary cancer-predisposing syndrome	2016-11-10	criteria provided, single submitter	clinical testing
Invitae	RCV003534420	SCV000768412	likely benign	Familial adenomatous polyposis 1	2024-01-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679047	SCV000805369	likely benign	not provided	2017-10-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162809	SCV002535157	likely benign	Hereditary cancer-predisposing syndrome	2021-03-12	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001085817	SCV001551164	uncertain significance	Familial adenomatous polyposis 1		no assertion criteria provided	clinical testing	The APC p.Leu519= variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, LOVD 3.0, UMD-LSDB, or the Zhejiang University database. The variant was identified in dbSNP (ID: rs765537673) as "With Likely benign allele", and in ClinVar (classified as likely benign by Ambry Genetics, Color Genomics, Invitae). The variant was identified in control databases in 2 of 245600 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 2 of 111198 chromosomes (freq: 0.00002), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu519= 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. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.