ClinVar Miner

Submissions for variant NM_000038.6(APC):c.317G>A (p.Arg106His) (rs201764637)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410470 SCV000489713 uncertain significance Familial adenomatous polyposis 1 2016-11-11 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000455267 SCV000538303 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband with cancer and a clinseq participant
Invitae RCV000410470 SCV000552490 uncertain significance Familial adenomatous polyposis 1 2018-09-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 106 of the APC protein (p.Arg106His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201764637, ExAC 0.03%). This variant has been reported in an individual affected with familial adenomatous polyposis (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 41524). 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, this variant has uncertain impact on APC function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000034409 SCV000566459 uncertain significance not provided 2018-11-30 criteria provided, single submitter clinical testing This variant is denoted APC c.317G>A at the cDNA level, p.Arg106His (R106H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been reported in at least one patient with FAP (Azzopardi 2008). APC Arg106His 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 Arg106His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000455267 SCV000600077 uncertain significance not specified 2017-06-16 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565565 SCV000667259 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000565565 SCV000681585 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000034409 SCV000694025 likely benign not provided 2016-08-01 criteria provided, single submitter clinical testing Variant summary: The APC c.317G>A (p.Arg106His) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome (MutationTaster and SNPs&GO not captured due to low reliability score/index). This variant was found in 6/124476 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.0003028 (5/16512). This frequency is about 4 times greater than the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. It has been reported in one colorectal adenoma sample in literature without strong evidence for or against pathogenicity (Azzopard_2008). Taken together, this variant is currently classified as Likely Benign.
Center for Human Genetics, Inc RCV000659270 SCV000781065 uncertain significance Familial adenomatous polyposis 2016-11-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034409 SCV000805390 uncertain significance not provided 2017-11-20 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034409 SCV000043102 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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