ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1984C>A (p.Leu662Ile) (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 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-20 criteria provided, single submitter clinical testing The p.L662I variant (also known as c.1984C>A), located in coding exon 15 of the APC gene, results from a C to A substitution at nucleotide position 1984. The leucine at codon 662 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in a proband with non-medullary thyroid cancer (Yu T et al. Sci Rep. 2015 Nov;5:16129). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000214596 SCV000537616 likely benign Hereditary cancer-predisposing syndrome 2019-12-19 criteria provided, single submitter clinical testing
Invitae RCV000474515 SCV000552537 likely benign Familial adenomatous polyposis 1 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000657144 SCV000571133 uncertain significance not provided 2017-06-23 criteria provided, single submitter clinical testing This variant is denoted APC c.1984C>A at the cDNA level, p.Leu662Ile (L662I) at the protein level, and results in the change of a Leucine to an Isoleucine (CTA>ATA). This variant has been reported in an individual with papillary thyroid cancer (Yu 2015). APC Leu662Ile was observed at an allele frequency of 0.08% (7/8576) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. APC Leu662Ile occurs at a position that is conserved across species and is located in the Armadillo region (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Leu662Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine,Partners HealthCare 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000657144 SCV001500348 uncertain significance not provided 2020-11-01 criteria provided, single submitter clinical testing
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 Rectal Adenocarcinoma 2017-03-20 no assertion criteria provided clinical testing

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