ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7594C>T (p.His2532Tyr) (rs375080917)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203815 SCV000260524 uncertain significance Familial adenomatous polyposis 1 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 2532 of the APC protein (p.His2532Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is present in population databases (rs375080917, ExAC 0.001%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 220176). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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 RCV000587117 SCV000567815 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing This variant is denoted APC c.7594C>T at the cDNA level, p.His2532Tyr (H2532Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAT>TAT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. APC His2532Tyr was not observed at a significant allele frequency 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 His2532Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000561106 SCV000667350 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000587117 SCV000694121 uncertain significance not provided 2016-06-20 criteria provided, single submitter clinical testing Variant summary: The APC c.7594C>T (p.His2532Tyr) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 1/121346 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).The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. It has been classified as VUS by one lab in ClinVar. The variant has been reported in the germline of a sample by a lab and as somatic occurrence in one endometrial cancer by COSMIC; both without strong evidence for or against pathogenicity. Because of lack of sufficient clinical information and functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000203815 SCV000785105 uncertain significance Familial adenomatous polyposis 1 2017-04-18 criteria provided, single submitter clinical testing
Color RCV000561106 SCV000909632 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing

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