ClinVar Miner

Submissions for variant NM_000038.6(APC):c.95A>G (p.Asn32Ser) (rs539108537)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204603 SCV000259432 uncertain significance Familial adenomatous polyposis 1 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 32 of the APC protein (p.Asn32Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs539108537, ExAC 0.02%). This variant has been reported in an individual affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 218010). 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. 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 RCV000656743 SCV000292446 uncertain significance not provided 2018-08-09 criteria provided, single submitter clinical testing This variant is denoted APC c.95A>G at the cDNA level, p.Asn32Ser (N32S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant was observed in at least one individual with colorectal cancer and in a breast cancer patient undergoing multi-gene panel testing (Tung 2016, Lee 2017). APC Asn32Ser was observed at an allele frequency of 0.02% (5/24,036) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the oligomerization domain (Azzopardi 2008). 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 Asn32Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569857 SCV000667217 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656743 SCV000887557 uncertain significance not provided 2018-11-05 criteria provided, single submitter clinical testing
Color RCV000569857 SCV000910900 likely benign Hereditary cancer-predisposing syndrome 2016-06-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000202147 SCV000916487 uncertain significance not specified 2017-10-20 criteria provided, single submitter clinical testing Variant summary: The APC c.95A>G (p.Asn32Ser) variant involves the alteration of a conserved nucleotide that lies within the adenomatous polyposis coli, N-terminal dimerisation domain (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 19/276974 control chromosomes from all ethnicities, but was observed in the African (0.000208) and East Asian (0.000159) subpopulations at frequencies that are 2-3 times above the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism. The variant has been found as a germline and somatic variant in patients with colorectal cancer, non-small cell lung cancer, and breast cancer, all without strong evidence for or against pathogenicity (Chang_2016, Lv_2017, Tung_2016). Multiple clinical diagnostic laboratories/reputable databases classified this variant as one of uncertain significance. Since the variant exceeds the maximal expected frequency of a pathogenic variant in two different subpopulations, this variant is classified as VUS-possibly normal until more information becomes available.
Mendelics RCV000204603 SCV001136868 uncertain significance Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202147 SCV000257039 uncertain significance not specified no assertion criteria provided research
3DMed Clinical Laboratory Inc RCV000677775 SCV000803931 uncertain significance Neoplasm of stomach 2018-01-25 no assertion criteria provided clinical testing

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