ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1441G>A (p.Val481Met) (rs587780542)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000119171 SCV000153901 uncertain significance Familial adenomatous polyposis 1 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 481 of the APC protein (p.Val481Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs587780542, ExAC 0.002%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 132722). 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 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.
Ambry Genetics RCV000164862 SCV000215546 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000585957 SCV000564565 uncertain significance not provided 2018-11-06 criteria provided, single submitter clinical testing This variant is denoted APC c.1441G>A at the cDNA level, p.Val481Met (V481M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. APC Val481Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the armadillo region (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Val481Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000164862 SCV000681461 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000585957 SCV000693997 uncertain significance not provided 2016-04-01 criteria provided, single submitter clinical testing Variant summary: The c.1441G>A variant affects a conserved nucleotide, resulting in amino acid change from Val to Met. 3/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). This variant is found in 1/120968 control chromosomes at a frequency of 0.0000083, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0000602). In addition, multiple clinical laboratories classified this variant as VUS. 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 was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000119171 SCV000785008 uncertain significance Familial adenomatous polyposis 1 2017-03-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585957 SCV001133299 uncertain significance not provided 2019-04-22 criteria provided, single submitter clinical testing
Mendelics RCV000119171 SCV001136884 uncertain significance Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing

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