ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1984C>A (p.Leu662Ile)

gnomAD frequency: 0.00002  dbSNP: rs756859993
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214596 SCV000276146 benign Hereditary cancer-predisposing syndrome 2021-03-31 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health RCV000214596 SCV000537616 likely benign Hereditary cancer-predisposing syndrome 2019-12-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000474515 SCV000552537 likely benign Familial adenomatous polyposis 1 2025-01-26 criteria provided, single submitter clinical testing
GeneDx RCV000657144 SCV000571133 likely benign not provided 2019-06-04 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26530882, 28195569, 30111351, 30833958, 27882345, 28944238, 28706299)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000483692 SCV000731488 uncertain significance not specified 2017-03-20 criteria provided, single submitter clinical testing The p.Leu662Ile variant in APC has not been previously reported in individuals w ith APC associated disorders, but has been identified in 7/8576 East Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs756859993). Computational prediction tools and conservation analysis d o not provide strong support for or against an impact to the protein. In summary , the clinical significance of the p.Leu662Ile variant is uncertain.
Counsyl RCV000474515 SCV000786467 uncertain significance Familial adenomatous polyposis 1 2018-05-08 criteria provided, single submitter clinical testing
Mendelics RCV000474515 SCV000838086 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000483692 SCV001361368 uncertain significance not specified 2019-06-17 criteria provided, single submitter clinical testing Variant summary: APC c.1984C>A (p.Leu662Ile) results in a conservative amino acid change located in the Armadillo repeat (IPR000225) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250674 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (6.8e-05 vs 7.1e-05), allowing no conclusion about variant significance. To our knowledge, c.1984C>A has not been reported in the literature in individuals affected with Familial Adenomatous Polyposis. This variant has been reported in individuals with familial non-medullary thyroid cancer (Yu_2015), metanephric adenoma (Ding_2018), esophageal squamous cell carcinoma (Deng_2019), and schozphrenia (Yang_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. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc. RCV000474515 SCV004019756 likely benign Familial adenomatous polyposis 1 2023-02-15 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
3DMed Clinical Laboratory Inc RCV000677741 SCV000803897 uncertain significance Duodenal adenocarcinoma 2017-03-20 no assertion criteria provided clinical testing
3DMed Clinical Laboratory Inc RCV000677742 SCV000803898 uncertain significance Rectum adenocarcinoma 2017-03-20 no assertion criteria provided clinical testing

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