ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6446A>C (p.His2149Pro) (rs749230730)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164369 SCV000215004 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000679080 SCV000293235 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing This variant is denoted APC c.6446A>C at the cDNA level, p.His2149Pro (H2149P) at the protein level, and results in the change of a Histidine to a Proline (CAT>CCT). This variant was observed in at least one individual described as having familial adenomatous polyposis (Azzopardi 2008), and in at least one individual with early-onset colorectal cancer (DeRycke 2017). APC His2149Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 His2149Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236978 SCV000600125 uncertain significance not specified 2017-02-21 criteria provided, single submitter clinical testing
Invitae RCV000545398 SCV000647643 uncertain significance Familial adenomatous polyposis 1 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 2149 of the APC protein (p.His2149Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with familial adenomatous polyposis (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 185017). 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: "Probably Damaging"; 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.
Counsyl RCV000545398 SCV000785093 uncertain significance Familial adenomatous polyposis 1 2018-05-15 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679080 SCV000805454 uncertain significance not provided 2018-01-10 criteria provided, single submitter clinical testing
Color RCV000164369 SCV000911741 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000236978 SCV000916490 uncertain significance not specified 2018-06-18 criteria provided, single submitter clinical testing Variant summary: APC c.6446A>C (p.His2149Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 276738 control chromosomes (in gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6446A>C has been reported in the literature in an individual affected with Familial Adenomatous Polyposis (Azzopardi 2008). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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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