ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5486A>G (p.Asn1829Ser) (rs767612847)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483629 SCV000566696 uncertain significance not provided 2016-10-12 criteria provided, single submitter clinical testing This variant is denoted APC c.5486A>G at the cDNA level, p.Asn1829Ser (N1829S) 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 Asn1829Ser 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 Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. APC Asn1829Ser occurs at a position where amino acids with properties similar to Asparagine are tolerated across species and is located within the 20-aa repeat Beta-catenin down regulating domain as well as 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 information, it is unclear whether APC Asn1829Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491516 SCV000579822 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000539969 SCV000647591 uncertain significance Familial adenomatous polyposis 1 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1829 of the APC protein (p.Asn1829Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs767612847, ExAC 0.03%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 419113). 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.
Color RCV000491516 SCV000909603 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing

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