ClinVar Miner

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

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Total submissions: 10
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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
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.
Color RCV000131637 SCV000902692 likely benign Hereditary cancer-predisposing syndrome 2016-03-22 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
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 uncertain significance Familial adenomatous polyposis 1 2018-07-03 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 2291 of the APC protein (p.Gln2291His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs148878262, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514) and in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 41534). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000211931 SCV000600140 uncertain significance not specified 2017-03-10 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000131637 SCV000787838 likely benign Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing

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