ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6873A>T (p.Gln2291His) (rs148878262)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131637 SCV000186661 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.
GeneDx RCV000034419 SCV000209541 likely benign not provided 2021-06-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22703879, 27443514, 28135145, 28873162, 27600092, 25479140)
Invitae RCV000168325 SCV000219012 likely benign Familial adenomatous polyposis 1 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000168325 SCV000488936 uncertain significance Familial adenomatous polyposis 1 2016-07-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034419 SCV000600140 likely benign not provided 2020-02-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211931 SCV000711422 uncertain significance not specified 2016-12-28 criteria provided, single submitter clinical testing The p.Gln2291His variant in APC has been reported in 1 individual with atheroscl erosis (Johnston 2012), but has also been identified in 14/66516 European chromo somes by the Exome Aggregation Consortium (ExAC,; dbSNP rs148878262). Computational prediction tools and conservation analysis su ggest that the p.Gln2291His variant may not impact the protein, though this info rmation is not predictive enough to rule out pathogenicity. This variant is list ed in ClinVar with multiple submitters classifying it as a variant of uncertain significance (ClinVar ID: 41534). In summary, the clinical significance of the p.Gln2291His variant is uncertain.
Color Health, Inc RCV000131637 SCV000902692 likely benign Hereditary cancer-predisposing syndrome 2016-03-22 criteria provided, single submitter clinical testing
Mendelics RCV000168325 SCV001136939 uncertain significance Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034419 SCV001154478 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001151804 SCV001312974 uncertain significance APC-Associated Polyposis Disorders 2018-01-12 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211931 SCV001361370 likely benign not specified 2020-08-23 criteria provided, single submitter clinical testing Variant summary: APC c.6873A>T (p.Gln2291His) results in a non-conservative amino acid change located in the basic domain (IPR009234) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 250976 control chromosomes, predominantly at a frequency of 0.00031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.3-fold the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.6873A>T has been reported in the literature in individuals affected with colorectal cancer (e.g. Yurgelun_2017), endometrial cancer (e.g. Ring_2016), pancreatic cancer (e.g. Grant_2015), and atherosclerosis (no information regarding cancer history, Johnson_2012). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; uncertain significance, n=7). Based on the evidence outlined above, the variant was classified as likely benign.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034419 SCV000043136 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353490 SCV000591204 likely benign Carcinoma of colon no assertion criteria provided clinical testing The APC p.Gln2291His variant was not identified in the literature nor was it identified in COSMIC, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database and UMD. The variant was identified in dbSNP (ID: rs148878262) “With other allele”, Clinvar database (with conflicting interpretations of pathogenicity, classified as benign by Ambry Genetics and uncertain significance by GeneDx, Invitae and Biesecker Laboratory-ClinSeq Project), and the Clinvitae database. This variant was also identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004), HAPMAP-EUR in 2 of 1006 chromosomes (frequency: 0.002), NHLBI GO Exome Sequencing Project (ESP) in 6 of 8600 European American alleles, and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 14 of 66516 chromosomes (frequency:0.0002)in the European (Non-Finnish) population. The p.Gln2291 residue is not conserved across mammals and the variant amino acid His is present in rat and hedgehog. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of 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 likely benign.
True Health Diagnostics RCV000131637 SCV000787838 likely benign Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000034419 SCV001740191 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000034419 SCV001807264 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000034419 SCV001922700 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000034419 SCV001951986 likely benign not provided no assertion criteria provided clinical testing

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