Submissions for variant NM_000038.6(APC):c.7862C>G (p.Ser2621Cys)

gnomAD frequency: 0.00358  dbSNP: rs72541816

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV000987588	SCV003836612	benign	Familial adenomatous polyposis 1	2023-02-26	reviewed by expert panel	curation	The c.7862C>G variant in APC is a missense variant predicted to cause the substitution of Serine by Cysteine at amino acid position 2621 (p.Ser2621Cys). This variant has been observed in more than 10 heterozygous individuals over the age of 50 with no features of FAP, worth more than 10 healthy individual points (BS2; Ambry internal data). APC is defined by the ClinGen APC VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.5021% in the non-Finnish European population, which is higher than the ClinGen APC VCEP threshold of 0.1% for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BA1, BS2, and BP1 (VCEP specifications version 1; date of approval: 12/12/2022).
Eurofins Ntd Llc (ga)	RCV000077995	SCV000109833	benign	not specified	2013-09-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130974	SCV000185889	benign	Hereditary cancer-predisposing syndrome	2014-11-28	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000077995	SCV000301607	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000367966	SCV000452050	benign	APC-Associated Polyposis Disorders	2018-03-06	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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034401	SCV000511737	likely benign	not provided	2017-01-24	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Invitae	RCV000987588	SCV000562659	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000077995	SCV000593260	benign	not specified	2019-10-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130974	SCV000681891	benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034401	SCV000885018	benign	not provided	2023-04-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000987588	SCV001136953	likely benign	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034401	SCV001154486	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	APC: BP4, BS1, BS2
GeneDx	RCV000034401	SCV001830306	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 27153395, 1316610, 24082139, 21859464, 24599579, 25260786, 22703879)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034401	SCV002011081	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130974	SCV002530900	benign	Hereditary cancer-predisposing syndrome	2020-05-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000077995	SCV002550666	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130974	SCV002819164	benign	Hereditary cancer-predisposing syndrome	2022-08-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000987588	SCV004015958	benign	Familial adenomatous polyposis 1	2023-07-07	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034401	SCV000043143	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000077995	SCV000084165	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353889	SCV000591216	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Ser2621Cys variant has been previously reported in the literature. From selected publications it was identified in 7 if 2428 case chromosomes (frequency: 0.0028) and 21 of 3670 control chromosomes (frequency: 0.0057), increasing the likelihood this is a benign polymorphism (Miyoshi_1992_1316610, Scott_2004_2839999, Ruiz-Ponte_2001_11668620, Azzopardi_2008_18199528, Lefevre_2012_22875147). In addition, it is reported with a frequency of 126/2172 control chromosomes from the 1000 genomes project and at a frequency of 0.005 in the European gohort ESP project database (dbSNPiD: rs72541816). Furthermore, 2 studies demonstrated non-segregation (Scott_2004_2839999, Ruiz-Ponte_2001_11668620) and the frequency of this variant was reported as higher in controls vs cases in two studies (Cancer Res-2008-Azzopardi-358-63_18199528, Lefevre_2012_jhg201299a_22875147), increasing the likelihood that this variant is benign. This variant is conserved in mammals but not lower organisms although it appears to not be located in an important functional domain, the creation of cystein residues, having a higher propensity for generating disulphide bonds, could in theory impact the protein. Computational analysis using several programs (SIFT, AlignGVGD, Polyphen-2, BLOSUM), do not agree on the imapact this variant change may have, and this information is not very predictive of pathogenicity. Based on the above information, this variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000077995	SCV000691769	benign	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000130974	SCV000805208	likely benign	Hereditary cancer-predisposing syndrome	2018-04-25	no assertion criteria provided	clinical testing