ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7264A>G (p.Thr2422Ala) (rs730881260)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590001 SCV000209546 uncertain significance not provided 2016-08-30 criteria provided, single submitter clinical testing This variant is denoted APC c.7264A>G at the cDNA level, p.Thr2422Ala (T2422A) 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 Thr2422Ala 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 Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Thr2422Ala occurs at a position that is conserved through mammals and is not located in a known functional 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 Thr2422Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000474958 SCV000552686 uncertain significance Familial adenomatous polyposis 1 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 2422 of the APC protein (p.Thr2422Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs730881260, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 181819). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000159571 SCV000600146 uncertain significance not specified 2017-03-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573375 SCV000667235 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000590001 SCV000694111 uncertain significance not provided 2017-07-28 criteria provided, single submitter clinical testing Variant summary: The APC c.7264A>G (p.Thr2422Ala) variant involves the alteration of a non-conserved nucleotide that lies within the adenomatous polyposis coli protein basic domain (InterPro). 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0000165 (2/120932 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, multiple clinical diagnostic laboratories have classified this variant as one of uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. An internal sample carries this variant along with a pathogenic RAD51C mutation (c.577C>T; p.R193X), suggesting the variant of interest may not be associated with the phenotype. However, 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.
Color RCV000573375 SCV000903822 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing

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