ClinVar Miner

Submissions for variant NM_000038.6(APC):c.8383G>A (p.Ala2795Thr) (rs369264968)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129383 SCV000184149 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-20 criteria provided, single submitter clinical testing The p.A2795T variant (also known as c.8383G>A), located in coding exon 15 of the APC gene, results from a G to A substitution at nucleotide position 8383. The alanine at codon 2795 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in one individual with multiple (between 11 and 99) colorectal adenomas (Azzopardi D et al. Cancer Res. 2008 Jan;68(2):358-63). Another study identified this alteration in one of 626 early-onset familial colorectal cancer cases (Chubb D et al. J. Clin. Oncol. 2015 Feb;33:426-32). This variant has also been seen in an exome cohort, but cancer history was not provided (Amendola LM et al. Genome Res. 2015 Mar;25:305-15). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000657075 SCV000293425 uncertain significance not provided 2018-11-27 criteria provided, single submitter clinical testing This variant is denoted APC c.8383G>A at the cDNA level, p.Ala2795Thr (A2795T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant was observed in at least one individual with a personal history of 11-99 colorectal adenomas and in at least one individual with a personal history of colorectal cancer (Azzopardi 2008, Chubb 2015). APC Ala2795Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). APC Ala2795Thr is located in the hDLG binding 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 Ala2795Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000410318 SCV000489112 uncertain significance Familial adenomatous polyposis 1 2016-08-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000235766 SCV000538301 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 1 VUS, 1 LB; Identified in one study in a group of patients designated as non-FAP/non-MAP but with 11-99 colorectal adenomas.
Invitae RCV000410318 SCV000552629 uncertain significance Familial adenomatous polyposis 1 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 2795 of the APC protein (p.Ala2795Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs369264968, ExAC 0.007%). This variant has been reported in individuals affected with colorectal adenomas and colorectal cancer (PMID: 18199528, 25559809). ClinVar contains an entry for this variant (Variation ID: 141047). 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 threonine 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.
Color Health, Inc RCV000129383 SCV000902938 likely benign Hereditary cancer-predisposing syndrome 2016-11-02 criteria provided, single submitter clinical testing
Mendelics RCV000410318 SCV001136959 benign Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000657075 SCV001154489 uncertain significance not provided 2018-09-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235766 SCV001361426 uncertain significance not specified 2020-10-09 criteria provided, single submitter clinical testing Variant summary: APC c.8383G>A (p.Ala2795Thr) results in a non-conservative amino acid change located in the EB-1 binding domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 244578 control chromosomes, predominantly at a frequency of 0.00017 within the East Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8383G>A has been reported in the literature in individuals affected with colorectal adenomas (Azzopardi_2008) and colorectal cancer (Chubb_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (uncertain significance, n=6; benign/likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
CSER _CC_NCGL, University of Washington RCV000148362 SCV000190052 likely benign Colorectal adenoma 2014-06-01 no assertion criteria provided research

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