ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3323A>G (p.Asn1108Ser) (rs151286353)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205736 SCV000261534 uncertain significance Familial adenomatous polyposis 1 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1108 of the APC protein (p.Asn1108Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs151286353, ExAC <0.01%). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 220743). 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 also 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. 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 RCV000236966 SCV000292731 uncertain significance not provided 2017-09-13 criteria provided, single submitter clinical testing This variant is denoted APC c.3323A>G at the cDNA level, p.Asn1108Ser (N1108S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been observed in at least one individual undergoing hereditary cancer panel testing for a personal history of a Lynch syndrome-associated cancer and/or colon polyps (Yurgelun 2015). APC Asn1108Ser was not observed at a significant allele frequency 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 Asn1108Ser occurs at a position where amino acids with properties similar to Asparagine are tolerated across species and is located within the beta-catenin 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 Asn1108Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000571447 SCV000667269 likely benign Hereditary cancer-predisposing syndrome 2017-09-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000571447 SCV000911099 likely benign Hereditary cancer-predisposing syndrome 2016-06-22 criteria provided, single submitter clinical testing

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