Submissions for variant NM_000038.6(APC):c.4893T>C (p.Ser1631=)

gnomAD frequency: 0.00268  dbSNP: rs35634377

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003315699	SCV000153822	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000211917	SCV000167010	benign	not specified	2014-04-08	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	RCV000123668	SCV000213278	likely benign	Hereditary cancer-predisposing syndrome	2014-08-01	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.
Illumina Laboratory Services, Illumina	RCV000388181	SCV000452016	likely benign	APC-Associated Polyposis Disorders	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000123668	SCV000681693	benign	Hereditary cancer-predisposing syndrome	2016-03-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586060	SCV000694060	benign	not provided	2016-01-25	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a non-conserved nucleotide and results in a synonymous mutation. Mutation taster predicts disease causing impact while 5/5 in silico tools via Alamut predict no significant effect on normal splicing. It was predominantly observed in the African subcohort of the ExAC project at an allele frequency of 0.538% which exeeds the maximal expected allele frequency of a disease causing APC allele 0.006% indicating a neutral impact. Additionally, clinical diagnostic centers classify variant as Likely Bening/Benign via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000211917	SCV000805415	benign	not specified	2017-06-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000211917	SCV000887525	benign	not specified	2021-09-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000211917	SCV002069706	benign	not specified	2019-07-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000123668	SCV002532688	benign	Hereditary cancer-predisposing syndrome	2020-11-25	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315699	SCV004015680	benign	Familial adenomatous polyposis 1	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211917	SCV004025070	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357649	SCV001553177	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Ser1631= variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs35634377) as "With other allele", and in ClinVar (classified as benign by Invitae, GeneDx, Color and three other submitters; and as likely benign by Ambry Genetics and two other submitters). The variant was identified in control databases in 211 of 276950 chromosomes at a frequency of 0.0008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 190 of 24022 chromosomes (freq: 0.008, increasing the likelihood this could be a low frequency benign variant), Other in 4 of 6460 chromosomes (freq: 0.0006), Latino in 16 of 34412 chromosomes (freq: 0.0005), and European in 1 of 126492 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser1631= 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) 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.