ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3949G>C (p.Glu1317Gln) (rs1801166)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 23
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 RCV000000872 SCV000153870 benign Familial adenomatous polyposis 1 2020-12-07 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000035073 SCV000226386 benign not specified 2014-12-03 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000035073 SCV000301593 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 RCV000035073 SCV000602523 benign not specified 2018-07-06 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034389 SCV000609169 likely benign not provided 2017-05-01 criteria provided, single submitter clinical testing
Color Health, Inc 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 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034389 SCV000888740 benign not provided 2018-03-23 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 uncertain significance not provided 2019-06-18 criteria provided, single submitter clinical testing
OMIM RCV000000872 SCV000021022 pathogenic Familial adenomatous polyposis 1 2000-09-22 no assertion criteria provided literature only
GeneReviews RCV000000872 SCV000040394 pathologic Familial adenomatous polyposis 1 2011-10-27 no assertion criteria provided curation Converted during submission to Pathogenic.
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
Mayo Clinic Laboratories, Mayo Clinic RCV000035073 SCV000256984 uncertain significance not specified 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.