ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5779C>A (p.Leu1927Ile) (rs730881253)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588338 SCV000209533 uncertain significance not provided 2017-12-28 criteria provided, single submitter clinical testing This variant is denoted APC c.5779C>A at the cDNA level, p.Leu1927Ile (L1927I) at the protein level, and results in the change of a Leucine to an Isoleucine (CTT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Leu1927Ile was not observed in large population cohorts (Lek 2016). APC Leu1927Ile is located within the 20-amino acid repeat beta-catenin down-regulating and SAMP repeats/axin binding domains (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 Leu1927Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000199957 SCV000254027 uncertain significance Familial adenomatous polyposis 1 2018-08-13 criteria provided, single submitter clinical testing This sequence change replaces leucine with isoleucine at codon 1927 of the APC protein (p.Leu1927Ile). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 181810). 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, 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.
Ambry Genetics RCV000218036 SCV000275411 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (benign)
Counsyl RCV000199957 SCV000489160 uncertain significance Familial adenomatous polyposis 1 2016-08-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588338 SCV000694084 uncertain significance not provided 2016-05-27 criteria provided, single submitter clinical testing Variant summary: The APC c.5779C>A (p.Leu1927Ile) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120712 control chromosomes. Multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color RCV000218036 SCV000911961 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-10 criteria provided, single submitter clinical testing

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