ClinVar Miner

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

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Total submissions: 14
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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
GeneDx RCV000034419 SCV000209541 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing This variant is denoted APC c.6873A>T at the cDNA level, p.Gln2291His (Q2291H) at the protein level, and results in the change of a Glutamine to a Histidine (CAA>CAT). This variant was observed to co-occur with APC Ile544Thr in individuals with endometrial or colorectal cancer (Ring 2016, Yurgelun 2017), as well as in 1/568 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). APC Gln2291His was observed at an allele frequency of 0.02% (14/66516) in individuals of European (Non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Gln2291His occurs at a position that is not conserved and is located within the Basic domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether APC Gln2291His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000168325 SCV000219012 likely benign Familial adenomatous polyposis 1 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000168325 SCV000488936 uncertain significance Familial adenomatous polyposis 1 2016-07-26 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000211931 SCV000591204 likely benign not specified 2016-09-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000211931 SCV000600140 uncertain significance not specified 2017-03-10 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 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.
Integrated Genetics/Laboratory Corporation of America 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.
True Health Diagnostics RCV000131637 SCV000787838 likely benign Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing

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