ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2725A>G (p.Thr909Ala) (rs878853430)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226462 SCV000282723 uncertain significance Familial adenomatous polyposis 1 2018-08-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 909 of the APC protein (p.Thr909Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 236578). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000767033 SCV000572333 uncertain significance not provided 2016-11-25 criteria provided, single submitter clinical testing This variant is denoted APC c.2725A>G at the cDNA level, p.Thr909Ala (T909A) at the protein level, and results in the change of a Threonine to an Alanine (ACC>GCC). APC Thr909Ala was observed as a germline variant in at least one patient with breast cancer undergoing hereditary cancer panel testing and as a confirmed somatic variant in a sporadic colorectal tumor (Christie 2013, Tung 2016). APC Thr909Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Thr909Ala occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether APC Thr909Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486036 SCV000600062 uncertain significance not specified 2017-04-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565184 SCV000667514 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000565184 SCV000911236 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing

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