Submissions for variant NM_000038.6(APC):c.7377T>C (p.Ser2459=)

gnomAD frequency: 0.00001  dbSNP: rs775573115

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003651914	SCV000562649	likely benign	Familial adenomatous polyposis 1	2023-02-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580788	SCV000681860	likely benign	Hereditary cancer-predisposing syndrome	2016-08-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000613898	SCV000727400	likely benign	not specified	2018-02-01	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	RCV000580788	SCV002672375	likely benign	Hereditary cancer-predisposing syndrome	2022-02-10	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.
PreventionGenetics, part of Exact Sciences	RCV003932765	SCV004758579	likely benign	APC-related condition	2019-12-23	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357623	SCV001553144	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The APC p.Ser2459= variant was not identified in the literature nor was it identified in the LOVD 3.0 and UMD-LSDB databases. The variant was identified in dbSNP (rs775573115) as “with likely benign allele” and ClinVar (classified as likely benign by Invitae, Color and GeneDx). The variant was identified in control databases in 2 of 251,004 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Latino population in 2 of 34,558 chromosomes (freq: 0.00006); it was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, European, Other or South Asian populations. The p.Ser2459= 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 at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.