Submissions for variant NM_000038.6(APC):c.3949G>C (p.Glu1317Gln)

gnomAD frequency: 0.00570  dbSNP: rs1801166

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035073	SCV000058713	benign	not specified	2020-07-01	criteria provided, single submitter	clinical testing	The p.Glu1317Gln variant in APC is classified as benign because of lack of conservation and it has been identified in 0.63% (810/128934, 7 homozygotes) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). While variant is present in >12 papers comments suggesting non-pathogenicity. ACMG/AMP Criteria applied: BA1, BP4.
Invitae	RCV003650352	SCV000153870	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000035073	SCV000167008	benign	not specified	2013-10-10	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.
Eurofins Ntd Llc (ga)	RCV000035073	SCV000226386	benign	not specified	2014-12-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000035073	SCV000301593	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000322880	SCV000452009	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034389	SCV000602523	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034389	SCV000609169	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	APC: BP4, BS1, BS2
Color Diagnostics, LLC DBA Color Health	RCV000579405	SCV000681643	benign	Hereditary cancer-predisposing syndrome	2020-11-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000000872	SCV000785169	likely benign	Familial adenomatous polyposis 1	2017-05-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000000872	SCV000838111	benign	Familial adenomatous polyposis 1	2023-08-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034389	SCV000888740	benign	not provided	2022-07-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579405	SCV001183123	likely benign	Hereditary cancer-predisposing syndrome	2019-12-26	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000034389	SCV001714746	benign	not provided	2019-06-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034389	SCV002010881	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000035073	SCV002069702	benign	not specified	2018-08-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000579405	SCV002536204	benign	Hereditary cancer-predisposing syndrome	2020-07-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000035073	SCV002550619	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000579405	SCV004015000	benign	Hereditary cancer-predisposing syndrome	2023-06-02	criteria provided, single submitter	clinical testing
OMIM	RCV000000872	SCV000021022	pathogenic	Familial adenomatous polyposis 1	2000-09-22	no assertion criteria provided	literature only
GeneReviews	RCV002286387	SCV000040394	not provided	Familial adenomatous polyposis 1		no assertion provided	literature only
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034389	SCV000043126	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000035073	SCV000084172	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000000872	SCV000189869	likely benign	Familial adenomatous polyposis 1	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353725	SCV000591162	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Glu1317Gln variant has been previously identified in the literature in 43/4470 (0.010) proband chromosomes and in 26/5002 (0.005) control chromosomes suggesting that this variant is a common variant observed 2 fold higher frequency in probands with attenuated FAP, FAP or multiple adenomas compared to controls (Aceto 2005, Curia 2012, Frayling 1998, Lamlum 2000, Plawski 2008, Azzopardi 2008, Hahnloser 2003, Liang 2013, Abdel-Malak 2015). One study demonstrated loss of heterozygosity in the colon cancer tumors in two individuals from the same family both retaining the variant, however segregation of this variant was not observed in two others with colorectal cancer in the same family and the although the family had multiple members affected with colon cancer their phenotypes were not consistent with FAP (White 1996). Further studies suggested the germline p.Glu1317Gln variant may provide a growth advantage for colorectal tumorigenesis when in combination with other weak mutant APC alleles (Dallosso 2009), but does not account for the occurrence of adenomas (Olschwang 2009 ). While some studies have suggested that the non-synonymous variant p.Glu1317Gln predisposes to multiple colorectal adenomas and CRCs (Lamlum 2000, Hahnloser 2003, Frayling 1998), other studies support a moderate increase in risk of CRC, or none ( Popat 2000, Zauber 2013, Rozek 2006). rnThe variant was identified in dbSNP (ID: rs1801166) “With other allele”, Clinvitae database (classified as benign and conflicting interpretations), COSMIC (in various tissues other than intestinal), InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), ClinVar database (classifications: benign by Invitae, GeneDX, Emory Genetics, Biesecker Laboratory; uncertain significance by Mayo Clinic and Laboratory for Molecular Medicine Partners HealthCare Personalized Medicine; pathogenic by OMIM and GeneReviews; and classification not provided by ITMI), GeneInsight - COGR database (classified as uncertain significance by a clinical laboratory), and UMD (5x with a “neutral” classification). The variant was identified by our laboratory in 6 individuals with colon or other cancers. The variant was identified in the 1000 Genomes Project in 15 of 5000 chromosomes (frequency: 0.003); HAPMAP-EUR in 6 of 1006 chromosomes (frequency: 0.006), HAPMAP-AFR in 4 of 1322 chromosomes (frequency: 0.003), HAPMAP-SAS in 3 of 978 chromosomes (frequency: 0.003); NHLBI Exome Sequencing Project (ESP) in 80 of 8600 European American (frequency 0.009) and in 28 of 4400 African American alleles (frequency 0.006); the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 500 of 121152 chromosomes (frequency: 0.0.004) (or 382 European individuals, 6 of which are homozygotes, 48 African, 4 Other, 32 Latino, 31 South Asian, 3 European (Finnish), increasing the likelihood this could be a low frequency benign variant. In addition we have observed this variant co-occuring with a known pathogenic variant (APC, c.3183_3187delACAAA) in a patient with confirmed FAP. The p.Glu1317 residue is mostly conserved in mammals with the variant amino acid Gln present in rat, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein, increasing the likelihood that this variant does not have clinical significance; however, this information is not predictive enough to rule out pathogenicity. 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 benign.
True Health Diagnostics	RCV000579405	SCV000693481	likely benign	Hereditary cancer-predisposing syndrome	2017-08-11	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000000872	SCV001190845	benign	Familial adenomatous polyposis 1	2020-02-05	no assertion criteria provided	clinical testing