ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1291A>G (p.Met431Val) (rs730881235)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656745 SCV000209492 uncertain significance not provided 2017-08-08 criteria provided, single submitter clinical testing This variant is denoted APC c.1291A>G at the cDNA level, p.Met431Val (M431V) 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 Met431Val was observed at an allele frequency of 0.003% (2/66254) in individuals of European (Non-Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. APC Met431Val occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is not located in a known functional domain. 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 Met431Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000230899 SCV000282693 uncertain significance Familial adenomatous polyposis 1 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 431 of the APC protein (p.Met431Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs730881235, ExAC 0.003%) but has not been reported in the literature in individuals with a APC-related disease. ClinVar contains an entry for this variant (Variation ID: 181787). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159532 SCV000600041 uncertain significance not specified 2017-06-13 criteria provided, single submitter clinical testing
Color RCV000579996 SCV000681452 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-17 criteria provided, single submitter clinical testing
Counsyl RCV000230899 SCV000784778 uncertain significance Familial adenomatous polyposis 1 2017-12-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000159532 SCV000918442 uncertain significance not specified 2018-05-25 criteria provided, single submitter clinical testing Variant summary: APC c.1291A>G (p.Met431Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 245540 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (2e-05 vs 7.1e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1291A>G in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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