Submissions for variant NM_000038.6(APC):c.993G>A (p.Ser331=)

gnomAD frequency: 0.00001  dbSNP: rs148343173

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166005	SCV000216764	likely benign	Hereditary cancer-predisposing syndrome	2014-10-09	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.
Counsyl	RCV000411887	SCV000488446	likely benign	Familial adenomatous polyposis 1	2016-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001704209	SCV000522138	likely benign	not provided	2018-11-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27693639)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411887	SCV000562631	likely benign	Familial adenomatous polyposis 1	2025-01-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166005	SCV000681941	likely benign	Hereditary cancer-predisposing syndrome	2016-08-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000433397	SCV001362377	benign	not specified	2019-05-17	criteria provided, single submitter	clinical testing	Variant summary: APC c.993G>A alters a non-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 variant allele was found at a frequency of 8e-05 in 251100 control chromosomes. The observed variant frequency is approximately 1.12 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 benign. To our knowledge, no occurrence of c.993G>A in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four 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 likely benign. Based on the evidence outlined above, the variant was classified as benign.
Myriad Genetics, Inc.	RCV000411887	SCV004017936	benign	Familial adenomatous polyposis 1	2023-02-16	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	RCV001358579	SCV001554360	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The APC p.Ser331= variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs148343173) as “with likely benign” allele, ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color, GeneDx and Counsyl) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 21 of 282,468 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 8 of 30,612 chromosomes (freq: 0.0003, increasing the likelihood this could be a low frequency benign variant), African in 6 of 24,956 chromosomes (freq: 0.0002), Latino in 3 of 35,418 chromosomes (freq: 0.00009), and European in 4 of 128,854 chromosomes (freq: 0.0003); it was not observed in the Ashkenazi Jewish, East Asian, Finnish or Other populations. The p.Ser331= 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.
PreventionGenetics, part of Exact Sciences	RCV003947428	SCV004770307	likely benign	APC-related disorder	2019-12-23	no assertion criteria provided	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).