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 benign Familial adenomatous polyposis 1 2019-12-30 criteria provided, single submitter clinical testing
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 2018-11-08 criteria provided, single submitter clinical testing 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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