ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4147A>G (p.Met1383Val) (rs1064793836)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478584 SCV000567150 uncertain significance not provided 2015-07-02 criteria provided, single submitter clinical testing This variant is denoted APC c.4147A>G at the cDNA level, p.Met1383Val (M1383V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Met1383Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Met1383Val occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located within a 20-aa repeat B-catenin down-regulating 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 Met1383Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573933 SCV000667441 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-08 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000573933 SCV000912140 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780866 SCV000918489 uncertain significance not specified 2018-09-07 criteria provided, single submitter clinical testing Variant summary: APC c.4147A>G (p.Met1383Val) results in a conservative amino acid change located in the Adenomatous polyposis coli protein repeat (IPR009223) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 30952 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4147A>G in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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