ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2461G>A (p.Val821Ile) (rs138498551)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159539 SCV000209501 uncertain significance not provided 2016-03-02 criteria provided, single submitter clinical testing This variant is denoted APC c.2461G>A at the cDNA level, p.Val821Ile (V821I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Val821Ile was was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. APC Val821Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located within the Ser-rich compositional bias region (UniProt). 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 Val821Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205053 SCV000261338 uncertain significance Familial adenomatous polyposis 1 2018-07-20 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 821 of the APC protein (p.Val821Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs138498551, ExAC 0.05%). This variant has not been reported in the literature in individuals with an APC-related disease. ClinVar contains an entry for this variant (Variation ID: 181793). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Counsyl RCV000205053 SCV000488774 uncertain significance Familial adenomatous polyposis 1 2016-06-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000572390 SCV000667481 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000572390 SCV000903454 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779726 SCV000916489 uncertain significance not specified 2018-06-15 criteria provided, single submitter clinical testing Variant summary: APC c.2461G>A (p.Val821Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 121132 control chromosomes. 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.2461G>A in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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