Submissions for variant NM_000038.6(APC):c.7821C>T (p.Ser2607=)

gnomAD frequency: 0.00002  dbSNP: rs532235331

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163955	SCV000214552	likely benign	Hereditary cancer-predisposing syndrome	2014-12-04	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198453	SCV000252595	benign	Familial adenomatous polyposis 1	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000310973	SCV000452049	benign	APC-Associated Polyposis Disorders	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Counsyl	RCV000198453	SCV000487782	likely benign	Familial adenomatous polyposis 1	2015-11-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000430616	SCV000512089	benign	not specified	2015-05-21	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.
Color Diagnostics, LLC DBA Color Health	RCV000163955	SCV000681888	benign	Hereditary cancer-predisposing syndrome	2016-11-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589014	SCV000694125	benign	not provided	2016-07-01	criteria provided, single submitter	clinical testing	Variant summary: The APC c.7821C>T (p.Ser2607Ser) causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 110/120952 (3 homozygotes, 1/1111), predominantly observed in the South Asian, 107/16502 (3 homozygotes, 1/154), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic APC variant of 1/14,0005 (0.0000714). Therefore, suggesting this variant is a common polymorphism found in population(s) of South Asian orign. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, although multiple reputable clinical laboratories cite the variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000430616	SCV000888769	benign	not specified	2021-11-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163955	SCV002530876	benign	Hereditary cancer-predisposing syndrome	2021-02-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000430616	SCV002550664	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000589014	SCV004011613	benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	APC: BP4, BP7, BS1, BS2
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000163955	SCV004014890	benign	Hereditary cancer-predisposing syndrome	2023-06-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000198453	SCV004018498	benign	Familial adenomatous polyposis 1	2023-02-17	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.
All of Us Research Program, National Institutes of Health	RCV003995298	SCV004835723	benign	Classic or attenuated familial adenomatous polyposis	2024-02-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000198453	SCV001549989	benign	Familial adenomatous polyposis 1		no assertion criteria provided	clinical testing	The APC p.Ser2607= variant was not identified in the literature nor was it identified in the following databases: COGR, Cosmic, MutDB, UMD-LSDB, and Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs532235331) “With other allele”, ClinVar (classified benign by Invitae, GeneDx and Quest Diagnostics Nichols Institute San Juan Capistrano; and likely benign by Ambry Genetics, Illumina and Counsyl), Clinvitae (4x), and in control databases in 182 (5 homozygous) of 276188 chromosomes at a frequency of 0.0007 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). Observations by population include African in 1 of 24008 chromosomes (freq. 0.00004), other in 3 of 6444 chromosomes (freq. 0.0005), Latino in 1 of 34310 chromosomes (freq. 0.002), European Non-Finnish in 1 of 126050 chromosomes (freq. 0.000008), East Asian in 2 of 18844 chromosomes (freq: 0.0001), and South Asian in 174 (5 homozygous) of 30656 chromosomes (freq. 0.0064); it was not seen in the Ashkenazi Jewish and European Finnish populations. The p.Ser2607= 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.