ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6688A>G (p.Met2230Val) (rs751547785)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485856 SCV000571274 uncertain significance not provided 2016-08-09 criteria provided, single submitter clinical testing This variant is denoted APC c.6688A>G at the cDNA level, p.Met2230Val (M2230V) 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 Met2230Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting 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 Met2230Val occurs at a position where amino acids with properties similar to Methionine 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 evidence, it is unclear whether APC Met2230Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000560933 SCV000667436 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000779720 SCV000916481 uncertain significance not specified 2017-11-20 criteria provided, single submitter clinical testing Variant summary: The APC c.6688A>G (p.Met2230Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/245786 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, one clinical diagnostic laboratory/reputable database classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. 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.
Invitae RCV000817518 SCV000958082 uncertain significance Familial adenomatous polyposis 1 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 2230 of the APC protein (p.Met2230Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs751547785, ExAC 0.009%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 421931). 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.

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