ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7109G>T (p.Gly2370Val) (rs140079759)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232680 SCV000282814 uncertain significance Familial adenomatous polyposis 1 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 2370 of the APC protein (p.Gly2370Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs140079759, ExAC 0.02%). This variant has been observed in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 236640). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; 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.
GeneDx RCV000236405 SCV000292908 uncertain significance not specified 2017-03-20 criteria provided, single submitter clinical testing This variant is denoted APC c.7109G>T at the cDNA level, p.Gly2370Val (G2370V) at the protein level, and results in the change of a Glycine to a Valine (GGT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Gly2370Val was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Gly2370Val occurs at a position where amino acids with properties similar to Glycine are tolerated across species and is located in the basic domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Gly2370Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569669 SCV000667254 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000236405 SCV000694108 likely benign not specified 2018-02-23 criteria provided, single submitter clinical testing Variant summary: APC c.7109G>T (p.Gly2370Val) alters a conserved nucleotide resulting in a non-conservative amino acid change located in the basic domain (IPR009234) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. However, the observed variant frequency within African control individuals in the gnomAD database is approximately 9 fold above the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The c.7109G>T variant has been reported in the literature in one individual with breast cancer (Tung 2015). This report does not provide strong evidence regarding an association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as uncertain significance. However, two of these laboratories cite the ESP and ExAC database control frequencies, both of which sample fewer individuals and show a lower frequency for the variant in the general population. Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV000569669 SCV000903488 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761101 SCV000891016 uncertain significance Retinoblastoma 2016-08-08 no assertion criteria provided clinical testing

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