ClinVar Miner

Submissions for variant NM_000038.6(APC):c.8057T>C (p.Val2686Ala) (rs757901425)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236452 SCV000292467 uncertain significance not provided 2016-03-10 criteria provided, single submitter clinical testing This variant is denoted APC c.8057T>C at the cDNA level, p.Val2686Ala (V2686A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Val2686Ala 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 Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. APC Val2686Ala occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the EB1 binding 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 Val2686Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000470997 SCV000552657 uncertain significance Familial adenomatous polyposis 1 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 2686 of the APC protein (p.Val2686Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs757901425, ExAC 0.003%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 243109). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant has uncertain impact on APC function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000561345 SCV000667373 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000561345 SCV000681907 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779729 SCV000916494 uncertain significance not specified 2018-07-02 criteria provided, single submitter clinical testing Variant summary: APC c.8057T>C (p.Val2686Ala) results in a non-conservative amino acid change located in the EB-1 binding of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246028 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.8057T>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four 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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