ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1984C>A (p.Leu662Ile) (rs756859993)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Ambry Genetics RCV000214596 SCV000276146 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Color RCV000214596 SCV000537616 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-18 criteria provided, single submitter clinical testing
Counsyl RCV000474515 SCV000786467 uncertain significance Familial adenomatous polyposis 1 2018-05-08 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.
Invitae RCV000474515 SCV000552537 uncertain significance Familial adenomatous polyposis 1 2018-05-11 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 662 of the APC protein (p.Leu662Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is present in population databases (rs756859993, ExAC 0.08%). This variant has been reported in an individual affected with non-medullary thyroid cancer (PMID: 26530882). ClinVar contains an entry for this variant (Variation ID: 232098). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
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.
Mendelics RCV000474515 SCV000838086 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing

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