ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7621A>G (p.Ile2541Val) (rs587778033)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589511 SCV000209471 uncertain significance not provided 2018-11-28 criteria provided, single submitter clinical testing This variant is denoted APC c.7621A>G at the cDNA level, p.Ile2541Val (I2541V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). While this variant has been observed in one individual with multiple colorectal adenomas, it has also been identified in 1 out of 331 healthy European individuals undergoing whole genome sequencing (Azzopardi 2008, Bodian 2014). APC Ile2541Val was observed at an allele frequency of 0.02% (6/30,780) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Ile2541Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000461123 SCV000552498 uncertain significance Familial adenomatous polyposis 1 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 2541 of the APC protein (p.Ile2541Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs587778033, ExAC 0.01%). This variant has been reported in an individual with colorectal adenomas (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 133514). 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 valine 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120020 SCV000591213 uncertain significance not specified 2015-12-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565915 SCV000667239 likely benign Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000589511 SCV000694122 uncertain significance not provided 2016-05-20 criteria provided, single submitter clinical testing Variant summary: The APC c.7621A>G (p.Ile2541Val) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured here due to low reliability index) predicting a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 7/123492 (1/17636; frequency of 0.0000567), predominantly observed in the European (Non-Finnish) cohort, 5/66712 (1/13342), which does exceed the estimated maximal expected allele frequency for a pathogenic APC variant of 1/17636 (0.0000714). Therefore, suggesting that the varinat is a rare polymorphism found in population(s) of European (Non-Finnish) origin. The variant of interest has been reported in affected individuals, although with limited information (ie lack of co-occurrence and cosegregation data), along with an internal LCA sample reporting the variant to co-occur with a deleterious BRCA2 variant, c.9117G>A (classified as pathogenic by LCA). In addition, multiple reputable databases/clinical laboratories have cited the variant with conflicting classifications "Neutral" or "Uncertain Signicance." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "VUS-possible benign," until addtional information becomes available.
PreventionGenetics,PreventionGenetics RCV000589511 SCV000805467 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing
Color RCV000565915 SCV000910824 likely benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
ITMI RCV000120020 SCV000084150 not provided not specified 2013-09-19 no assertion provided reference population

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