ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5879_5880delinsTA (p.Pro1960Leu) (rs587779801)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115107 SCV000149016 uncertain significance not provided 2018-08-03 criteria provided, single submitter clinical testing This variant is denoted APC c.5879_5880delCGinsTA at the cDNA level and p.Pro1960Leu (P1960L) at the protein level. The surrounding sequence is ACTC[delCG][insTA]GTTT. This in-frame deletion and insertion results in the missense change of a Proline to a Leucine (CCG>CTA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. Another variant resulting in the same amino acid substitution, APC c.5879C>T (p.Pro1960Leu), has been reported in at least two individuals with colon cancer (Pearlman 2016, Yurgelun 2017). Neither APC c.5879_5880delCGinsTA nor APC Pro1960Leu was observed in large population cohorts (Lek 2016). This variant is located in the 20-amino acid repeat beta-catenin down-regulating domain as well as the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether APC c.5879_5880delCGinsTA is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000232068 SCV000282785 uncertain significance Familial adenomatous polyposis 1 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1960 of the APC protein (p.Pro1960Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is reported as two separate single-nucleotide changes in population databases (c.5879C>T, ExAC 0.003% and c.5880G>A, ExAC 65%). However, in the read data for 4/5 individuals displayed in the ExAC browser, these two variants are in cis. This recapitulates the variant observed here (c.5879_5880delCGinsTA) and indicates that this variant is very likely present in the population databases at 0.003%. This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 127309). 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 15"). 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 RCV000232068 SCV000488890 uncertain significance Familial adenomatous polyposis 1 2016-07-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000491906 SCV000579869 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Co-occurence with mutation in same gene (phase unknown),Insufficient evidence
Color RCV000491906 SCV000681766 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115107 SCV000888751 uncertain significance not provided 2017-10-18 criteria provided, single submitter clinical testing

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