ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4918C>T (p.Arg1640Trp) (rs373440614)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131255 SCV000186218 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000587871 SCV000209528 uncertain significance not provided 2018-12-06 criteria provided, single submitter clinical testing This variant is denoted APC c.4918C>T at the cDNA level, p.Arg1640Trp (R1640W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been observed in at least one individual meeting diagnostic criteria for familial adenomatous polyposis (Scott 2004). APC Arg1640Trp was observed at an allele frequency of 0.014% (18/126,442) in individuals of European ancestry in large population cohorts (Lek 2016). APC Arg1640Trp is located in the SAMP repeats/axin binding domain and a Beta-catenin down-regulating domain (Azzopardi 2008). 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 Arg1640Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000148368 SCV000282767 uncertain significance Familial adenomatous polyposis 1 2018-11-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 1640 of the APC protein (p.Arg1640Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs373440614, ExAC 0.01%). This variant has been reported in an individual and multiple affected members of the same family with familial adenomatous polyposis (FAP) (PMID: 7833931, 20233475). This variant is also known as 4921C>T, Arg1841Trp in the literature. ClinVar contains an entry for this variant (Variation ID: 142246). 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 disruptive, but these predictions have not been confirmed by published functional studies. 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.
Color RCV000131255 SCV000681696 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587871 SCV000694064 uncertain significance not provided 2017-03-24 criteria provided, single submitter clinical testing Variant summary: The c.4918C>T (p.Arg1460Trp) in APC gene is a missense change that involves a non-conserved nucleotide and 4/4 in silico tools predict deleterious outcome. The variant of interest is located within conserved APC cysteine-rich repeat, that is required for binding beta-catenin, however no studies determining the functional impact of this variant have been conducted and published at the time of evaluation. The variant is present in the large control population dataset of ExAC and gnomAD at a similar frequencies of 0.00007 (9/121356 and 20/276908 chrs tested, respectively), predominantly in individuals of European descent (0.00014; 8/66712 and 18//126442 chrs tested) which exceeds the maximal expected frequency of a pathogenic allele (0.000071) in this gene. The variant has been reported in at least 1 FAP family and was shown to segregate with disease in all affected individuals in this family with the later onset (mean age of dx = 37years). Lastly, several reputable databases/clinical laboratories cite the variant with classification of VUS. Taking all line of evidence into consideration, the variant was conservatively classified as VUS-Possibly Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587871 SCV000887527 uncertain significance not provided 2017-09-06 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148368 SCV000190060 uncertain significance Familial adenomatous polyposis 1 2014-06-01 no assertion criteria provided research

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