ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6639G>A (p.Met2213Ile) (rs35540155)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130211 SCV000185049 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000409211 SCV000488876 uncertain significance Familial adenomatous polyposis 1 2016-07-18 criteria provided, single submitter clinical testing
Invitae RCV000409211 SCV000552646 uncertain significance Familial adenomatous polyposis 1 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 2213 of the APC protein (p.Met2213Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs35540155, ExAC 0.006%). This variant has been reported in an individual undergoing testing for Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 141618). 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 isoleucine 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 and their clinical significance is uncertain. 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.
GeneDx RCV000484737 SCV000566001 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing This variant is denoted APC c.6639G>A at the cDNA level, p.Met2213Ile (M2213I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant was observed in an individual with a Lynch syndrome-related cancer and/or polyps undergoing multigene hereditary cancer panel testing as well as at least one individual from the general Qatari population undergoing whole exome sequencing (Rodriguez-Flores 2014, Yurgelun 2015). APC Met2213Ile was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. APC Met2213Ile occurs at a position that is not conserved and is located in the Basic domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether APC Met2213Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000130211 SCV000821822 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765788 SCV000897177 uncertain significance Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000130211 SCV000910766 likely benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001157265 SCV001318816 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.