ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2110G>A (p.Val704Ile) (rs367804502)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164801 SCV000215481 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Invitae RCV000198244 SCV000253995 uncertain significance Familial adenomatous polyposis 1 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 704 of the APC protein (p.Val704Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs367804502, ExAC 0.01%). This variant has been observed in an individual with numerous colon polyps and other cancers (Invitae). However, in that individual a pathogenic allele was also identified in the APC gene, which suggests that this c.2110G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 185391). 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: "Possibly 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.
GeneDx RCV000657054 SCV000293114 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing This variant is denoted APC c.2110G>A at the cDNA level, p.Val704Ile (V704I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Val704Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. APC Val704Ile is located within the Armadillo region (Azzopardi 2008). 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 Val704Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236550 SCV000600056 uncertain significance not specified 2017-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000198244 SCV000785203 uncertain significance Familial adenomatous polyposis 1 2017-06-02 criteria provided, single submitter clinical testing
Mendelics RCV000198244 SCV000838087 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000236550 SCV000916473 uncertain significance not specified 2017-11-20 criteria provided, single submitter clinical testing Variant summary: The APC c.2110G>A (p.Val704Ile) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 5/276452 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.000167 (4/23992). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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