ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5027G>C (p.Arg1676Thr) (rs143674116)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130120 SCV000184952 likely benign Hereditary cancer-predisposing syndrome 2017-12-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance,Subpopulation frequency in support of benign classification
GeneDx RCV000589678 SCV000292990 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing This variant is denoted APC c.5027G>C at the cDNA level, p.Arg1676Thr (R1676T) at the protein level, and results in the change of an Arginine to a Threonine (AGA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Arg1676Thr was observed at an allele frequency of 0.12% (12/10,280) in individuals of African ancestry in large population cohorts (Lek 2016). Since Arginine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Arg1676Thr occurs at a position that is not conserved and is located in a beta-catenin down-regulating domain and the SAMP repeats/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 Arg1676Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000459029 SCV000552750 likely benign Familial adenomatous polyposis 1 2018-01-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000722124 SCV000694068 likely benign not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: APC c.5027G>C (p.Arg1676Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.8e-05 in 275926 control chromosomes. The observed variant frequency is approximately 1.37 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is benign. Furthermore, the observed variant frequency within African control individuals in the gnomAD database is approximately 15.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no germline occurrence of c.5027G>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four 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 (2 likely benign and 2 VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV000130120 SCV000902908 likely benign Hereditary cancer-predisposing syndrome 2016-03-18 criteria provided, single submitter clinical testing

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