ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5635G>T (p.Ala1879Ser) (rs587779799)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115105 SCV000149014 uncertain significance not specified 2017-08-22 criteria provided, single submitter clinical testing This variant is denoted APC c.5635G>T at the cDNA level, p.Ala1879Ser (A1879S) at the protein level, and results in the change of an Alanine to a Serine (GCT>TCT). This variant has been identified in at least one individual with a Lynch syndrome-associated cancer and/or polyps and in a pediatric patient with hyperdiploid acute lymphoblastic leukemia (Yurgelun 2015, Zhang 2015). APC Ala1879Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Ala1879Ser occurs at a position that is conserved through mammals and is located in the 20-amino acid repeat beta-catenin down-regulating domain and SAMP repeat/axin binding domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Ala1879Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204622 SCV000260105 uncertain significance Familial adenomatous polyposis 1 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 1879 of the APC protein (p.Ala1879Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs587779799, ExAC 0.002%). This variant has been reported in an individual with a Lynch syndrome-associated cancer or colorectal polyps (PMID: 25980754) and in an individual affected with acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 127307). 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: "Benign"; Align-GVGD: "Class C65"). 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 RCV000204622 SCV000488557 uncertain significance Familial adenomatous polyposis 1 2016-05-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000575966 SCV000667261 likely benign Hereditary cancer-predisposing syndrome 2018-04-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (benign),Other data supporting benign classification
Color RCV000575966 SCV000681754 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759434 SCV000888748 uncertain significance not provided 2017-10-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000115105 SCV000916479 uncertain significance not specified 2018-02-09 criteria provided, single submitter clinical testing Variant summary: APC c.5635G>T (p.Ala1879Ser) results in a conservative amino acid change in the encoded protein sequence and three of five in-silico tools predict a benign effect of the variant on protein function. However, these predictions have yet to be functionally assessed. The variant, c.5635G>T, was observed with an allele frequency of 0.00002169 in 276676 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (2.2e-05 vs 7.1e-05), allowing no conclusion about variant significance. The variant, c.5635G>T, was observed in 1 Lynch syndrome patient (Yurgelun_2015) and 1 Hyperdiploid ALL (Zhang_2015), with limited information (i.e., lack of co-segregation and/or co-occurrence data). Multiple clinical diagnostic laboratories via ClinVar submission (evaluations after 2014) have conflicting classifications from "likely benign" to "uncertain significance". Based on the evidence outlined above, the variant was classified as uncertain significance.

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