ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5147A>G (p.Asn1716Ser) (rs141298709)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465464 SCV000552516 uncertain significance Familial adenomatous polyposis 1 2018-03-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1716 of the APC protein (p.Asn1716Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs141298709, 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: 411385). 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 serine 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. 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.
GeneDx RCV000481145 SCV000567743 uncertain significance not provided 2017-08-25 criteria provided, single submitter clinical testing This variant is denoted APC c.5147A>G at the cDNA level, p.Asn1716Ser (N1716S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Asn1716Ser was observed at an allele frequency of 0.012% (2/16,462) in individuals of South Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. APC Asn1716Ser occurs at a position that is not conserved and is located in the 20-amino acid repeat B-catenin down-regulating domain and 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 Asn1716Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572058 SCV000667223 likely benign Hereditary cancer-predisposing syndrome 2017-08-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Counsyl RCV000465464 SCV000785395 uncertain significance Familial adenomatous polyposis 1 2017-07-24 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000481145 SCV000805423 uncertain significance not provided 2017-08-10 criteria provided, single submitter clinical testing
Color RCV000572058 SCV000903273 likely benign Hereditary cancer-predisposing syndrome 2016-07-05 criteria provided, single submitter clinical testing

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