ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5839A>G (p.Thr1947Ala) (rs746346292)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164466 SCV000215110 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000206414 SCV000260610 uncertain significance Familial adenomatous polyposis 1 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1947 of the APC protein (p.Thr1947Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs746346292, ExAC 0.002%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 185103). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Counsyl RCV000206414 SCV000487773 uncertain significance Familial adenomatous polyposis 1 2015-11-23 criteria provided, single submitter clinical testing
GeneDx RCV000483817 SCV000566822 uncertain significance not provided 2017-04-21 criteria provided, single submitter clinical testing This variant is denoted APC c.5839A>G at the cDNA level, p.Thr1947Ala (T1947A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Thr1947Ala was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Thr1947Ala occurs at a position that is not conserved and is located in the B-catenin down-regulating domain and the SAMP repeats/axin binding domain (Azzopardi 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether APC Thr1947Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000164466 SCV000911739 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779706 SCV000916460 uncertain significance not specified 2017-12-04 criteria provided, single submitter clinical testing Variant summary: The APC c.5839A>G (p.Thr1947Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 6/276170 control chromosomes at a frequency of 0.0000217, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. 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 is classified as a variant of uncertain significance (VUS) until additional information becomes available.

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