ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1241G>A (p.Arg414His) (rs730881233)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159530 SCV000209490 uncertain significance not provided 2017-06-27 criteria provided, single submitter clinical testing This variant is denoted APC c.1241G>A at the cDNA level, p.Arg414His (R414H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Arg414His was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. APC Arg414His occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether APC Arg414His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227001 SCV000282692 uncertain significance Familial adenomatous polyposis 1 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 414 of the APC protein (p.Arg414His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs730881233, ExAC 0.02%). This variant has been reported in an individual affected with neuroblastoma (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 181785). 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 RCV000227001 SCV000489182 uncertain significance Familial adenomatous polyposis 1 2016-08-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000568544 SCV000667237 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
PreventionGenetics,PreventionGenetics RCV000159530 SCV000805366 uncertain significance not provided 2017-09-01 criteria provided, single submitter clinical testing
Color RCV000568544 SCV000905879 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779739 SCV000916511 uncertain significance not specified 2018-11-16 criteria provided, single submitter clinical testing Variant summary: APC c.1241G>A (p.Arg414His) 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 3.3e-05 in 245360 control chromosomes, predominantly at a frequency of 0.00021 within the Latino subpopulation in the gnomAD database, which is 3-folds over the estimated maximum expected allele frequency for a pathogenic APC variant. Therefore, suggesting the variant is a benign polymorphism found predominantly in population(s) of Latino origin. c.1241G>A has not been reported in the literature in individuals affected with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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