ClinVar Miner

Submissions for variant NM_000038.6(APC):c.6019T>C (p.Tyr2007His) (rs745811356)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464146 SCV000552690 uncertain significance Familial adenomatous polyposis 1 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 2007 of the APC protein (p.Tyr2007His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs745811356, ExAC 0.006%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 411501). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000590075 SCV000567455 uncertain significance not provided 2017-11-02 criteria provided, single submitter clinical testing This variant is denoted APC c.6019T>C at the cDNA level, p.Tyr2007His (Y2007H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Tyr2007His was not observed at a significant frequency in large population cohorts (Lek 2016). Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Tyr2007His occurs at a position that is conserved across species and is located in the SAMP repeats/Axin binding domain and beta catenin down-regulating 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 Tyr2007His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000561606 SCV000667270 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000561606 SCV000681774 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855566 SCV000694088 uncertain significance not specified 2019-04-15 criteria provided, single submitter clinical testing Variant summary: APC c.6019T>C (p.Tyr2007His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250120 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6019T>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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