ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2658G>T (p.Gln886His) (rs587780593)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122768 SCV000166025 uncertain significance Familial adenomatous polyposis 1 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 886 of the APC protein (p.Gln886His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 135694). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Counsyl RCV000122768 SCV000488361 uncertain significance Familial adenomatous polyposis 1 2016-03-08 criteria provided, single submitter clinical testing
GeneDx RCV000485846 SCV000566342 uncertain significance not specified 2017-05-22 criteria provided, single submitter clinical testing This variant is denoted APC c.2658G>T at the cDNA level, p.Gln886His (Q886H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Gln886His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Gln886His occurs at a position that is conserved through mammals and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether APC Gln886His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574171 SCV000667464 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-23 criteria provided, single submitter clinical testing Insufficient evidence
University of Washington Department of Laboratory Medicine, University of Washington RCV000664308 SCV000788240 likely benign Familial multiple polyposis syndrome 2018-04-01 criteria provided, single submitter research The APC variant designated as NM_000038.5:c.2658G>T (p.Gln886His) is classified as likely benign. This variant was observed in an individual in one family who was documented not to have colon polyps on colonoscopy at over 70 years old. This observation is not consistent with either attenuated or classic familial adenomatous polyposis syndromes (Grover et al. 2012, PMID:22851115). Additional family members at risk of inheriting the variant have been documented to have no colon polyps. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a <1% probability of pathogenicity, which is consistent with a classification of likely benign. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Color RCV000574171 SCV000905973 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001157044 SCV001318590 uncertain significance APC-Associated Polyposis Disorders 2018-01-13 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.

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.