ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3275A>C (p.His1092Pro) (rs587779788)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115080 SCV000148989 uncertain significance not provided 2014-01-02 criteria provided, single submitter clinical testing This variant is denoted APC c.3275A>C at the cDNA level, p.His1092Pro (H1092P) at the protein level, and results in the change of a Histidine to a Proline (CAT>CCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC His1092Pro 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. This variant is a non-conservative substitution in which a positive polar amino acid is replaced with a neutral non-polar one, altering a position that is well conserved throughout evolution and is located in the region responsible for down-regulation through ubiquitination (UniProt). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC His1092Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000412266 SCV000488020 uncertain significance Familial adenomatous polyposis 1 2015-12-18 criteria provided, single submitter clinical testing
Invitae RCV000412266 SCV000647437 uncertain significance Familial adenomatous polyposis 1 2017-05-11 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 1092 of the APC protein (p.His1092Pro). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and proline. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a APC-related disease. ClinVar contains an entry for this variant (Variation ID: 127286). 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.
Ambry Genetics RCV000570435 SCV000667592 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Mendelics RCV000412266 SCV000838102 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing

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