ClinVar Miner

Submissions for variant NM_000038.5(APC):c.2438A>G (p.Asn813Ser) (rs201522866)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162586 SCV000213002 likely benign Hereditary cancer-predisposing syndrome 2018-02-22 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,Other data supporting benign classification
Biesecker Lab/Human Development Section,National Institutes of Health RCV000034381 SCV000043115 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000162586 SCV000910723 likely benign Hereditary cancer-predisposing syndrome 2016-11-10 criteria provided, single submitter clinical testing
GeneDx RCV000034381 SCV000293555 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing This variant is denoted APC c.2438A>G at the cDNA level, p.Asn813Ser (N813S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been observed in an individual with colorectal cancer and in another with a personal and family history of pancreatic cancer (Yurgelun 2017, Chaffee 2018). Additionally, APC Asn813Ser was studied in a melanoma cell line, which displayed no increase of Axin2 expression and no increase of Wnt signaling (Worm 2004). APC Asn813Ser was observed at an allele frequency of 0.02% (5/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Asn813Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000034381 SCV000694013 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing Variant summary: The APC c.2438A>G (p.Asn813Ser) variant involves the alteration of a non-conserved nucleotide, which 3/3 in silico tools (SNPs&GO and MutationTaster are not captured due to low reliability index and p-value)predict a benign outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 7/121156 (1/17292), which does not exceed the estimated maximal expected allele frequency for a pathogenic APC variant of 1/14005. The variant of interest has been reported in multiple publications including a tumour sample (although not germline confirmed). A functional study indicates the variant does not affect downstream targets in the WNT pathway and therefore the authors suggest this variant does not affect APC protein function, however, the implications of the WNT pathway and tumorigenesis have yet to be functionally established. In addition, multiple clinical diagnostic laboratories cite the variant as "uncertain significance." Therefore, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Invitae RCV000195489 SCV000253999 uncertain significance Familial adenomatous polyposis 1 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 813 of the APC protein (p.Asn813Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs201522866, ExAC 0.02%). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 41499). Experimental studies with melanoma cell lines have shown that this missense change does not increase the expression of downstream products in the Wnt signaling pathway, and therefore is not predicted to functionally affect the activity of the APC protein (PMID: 15133491). 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.
PreventionGenetics RCV000034381 SCV000805380 uncertain significance not provided 2017-01-31 criteria provided, single submitter clinical testing

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