ClinVar Miner

Submissions for variant NM_000038.6(APC):c.681C>G (p.Asp227Glu) (rs1060503359)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000476893 SCV000552735 uncertain significance Familial adenomatous polyposis 1 2018-04-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 227 of the APC protein (p.Asp227Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 411535). 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 and their clinical significance is uncertain. 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 RCV000572312 SCV000667246 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Institute of Human Genetics,University of Goettingen RCV000476893 SCV000994922 uncertain significance Familial adenomatous polyposis 1 2019-10-02 criteria provided, single submitter clinical testing For the following reasons, the APC sequence variant c.681C>G (p.Asp227Glu) is assessed by us as a "variant of uncertain significance" (VUS) with possibly benign character: 1. a comparison with the ExAC and gnomAD databases did not provide any indication that this sequence change is a norm variant that can also be detected in non-affected individuals (gnomAD population frequecy: 0.0004%); 2. the variant is listed twice in ClinVar as a VUS; 3. the variant has a benign computational verdict due to 9 benign predictions from DANN, DEOGEN2, FATHMM-XF, GERP, MutationAssessor, PROVEAN, PrimateAI, SIFT and SIFT4G vs. 5 pathogenic predictions from FATHMM, FATHMM-MKL, LRT, M-CAP and MutationTaster; 4. the position of this variant is not conserved; 5. the base exchange leads to a missense mutation in the APC gene; most of the described pathogenic mutations in the APC gene are frame shift and nonsense mutations.

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