ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2209T>C (p.Tyr737His) (rs748868815)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480278 SCV000565805 uncertain significance not provided 2015-03-05 criteria provided, single submitter clinical testing This variant is denoted APC c.2209T>C at the cDNA level, p.Tyr737His (Y737H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Tyr737His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Tyr737His occurs at a position that is conserved across species and is located in the 7th armadillo repeat region (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 Tyr737His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000580908 SCV000681508 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-03 criteria provided, single submitter clinical testing
Invitae RCV000646446 SCV000768218 uncertain significance Familial adenomatous polyposis 1 2017-11-17 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 737 of the APC protein (p.Tyr737His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs748868815, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 418611). 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 C0"). 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.

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