ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5282A>C (p.Asn1761Thr) (rs752038930)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230741 SCV000282776 uncertain significance Familial adenomatous polyposis 1 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with threonine at codon 1761 of the APC protein (p.Asn1761Thr). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with APC-related disease. However, it has been reported in a healthy control individual (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 236617). 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.
Counsyl RCV000230741 SCV000488791 uncertain significance Familial adenomatous polyposis 1 2016-06-16 criteria provided, single submitter clinical testing
GeneDx RCV000586532 SCV000566475 uncertain significance not provided 2018-08-21 criteria provided, single submitter clinical testing This variant is denoted APC c.5282A>C at the cDNA level, p.Asn1761Thr (N1761T) at the protein level, and results in the change of an Asparagine to a Threonine (AAC>ACC). This variant was absent in a series of patients with a history of colorectal adenomas (0/691) and observed once in a healthy control (1/969), who also had the APC variants T1633K and T1655A (Azzopardi 2008). APC Asn1761Thr was also observed along with APC Thr1655Ala in an individual with breast cancer who was undergoing hereditary cancer panel testing (Tung 2015). APC Asn1761Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). APC Asn1761Thr is located within the beta-catenin down-regulating domain and the SAMP repeats/axin binding 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 Asn1761Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573026 SCV000667458 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000573026 SCV000681727 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586532 SCV000694072 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The APC c.5282A>C (p.Asn1761Thr) variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 1/122416 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
PreventionGenetics,PreventionGenetics RCV000586532 SCV000805429 uncertain significance not provided 2017-07-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586532 SCV000887536 uncertain significance not provided 2017-08-31 criteria provided, single submitter clinical testing

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