ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4072G>A (p.Ala1358Thr) (rs139618756)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129585 SCV000184368 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000588058 SCV000209521 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing This variant is denoted APC c.4072G>A at the cDNA level, p.Ala1358Thr (A1358T) at the protein level, and results in the change of an Alanine to a Threonine (GCG>ACG). This variant has been observed in at least three individuals with colon cancer, in two pediatric patients with acute leukemia, and in individuals with breast or kidney cancer (Tung 2015, Zhang 2015, Raskin 2017, Yurgelun 2017, Yehia 2018). APC Ala1358Thr was observed at an allele frequency of 0.01% (18/126,066) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the 20-amino acid repeat 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 Ala1358Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000167896 SCV000218542 uncertain significance Familial adenomatous polyposis 1 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1358 of the APC protein (p.Ala1358Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs139618756, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer, colorectal cancer and suspected Lynch syndrome (PMID: 25186627, 25980754, 28135145, 29212164). ClinVar contains an entry for this variant (Variation ID: 141191). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000167896 SCV000488249 uncertain significance Familial adenomatous polyposis 1 2016-02-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000211912 SCV000600094 uncertain significance not specified 2017-01-11 criteria provided, single submitter clinical testing
Color RCV000129585 SCV000681645 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588058 SCV000694044 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing Variant summary: The APC c.4072G>A (p.Ala1358Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 8/121152 control chromosomes, exclusivetly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0001201 (8/66612). This frequency is slightly higher than the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this may be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. This variant has been reported in multiple cancer patients (Kanojia_2015, Yurgelun_2015) without sufficient evidence to prove causation. Taken together, this variant is classified as VUS.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000211912 SCV000691745 uncertain significance not specified no assertion criteria provided clinical testing

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