ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7888G>A (p.Val2630Ile) (rs199688874)

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
GeneDx RCV000254630 SCV000149033 likely benign not specified 2017-09-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115124 SCV000184471 likely benign Hereditary cancer-predisposing syndrome 2017-03-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Counsyl RCV000409244 SCV000488215 uncertain significance Familial adenomatous polyposis 1 2016-01-27 criteria provided, single submitter clinical testing
Invitae RCV000409244 SCV000552684 uncertain significance Familial adenomatous polyposis 1 2018-12-16 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2630 of the APC protein (p.Val2630Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs199688874, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 41517). 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.
Mendelics RCV000409244 SCV000838157 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000115124 SCV000910742 likely benign Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000254630 SCV000918437 likely benign not specified 2018-04-23 criteria provided, single submitter clinical testing Variant summary: APC c.7888G>A (p.Val2630Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was observed with an allele frequency of 0.0001 in 245888 control chromosomes (gnomAD). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3-folds higher than 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. The variant, c.7888G>A, has been reported in the literature in a validation study (Rey_2017). These report(s) 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. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance" (2x) or "likely benign" (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034402 SCV000043144 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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.