ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1040C>G (p.Ala347Gly) (rs587782058)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130534 SCV000185403 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000217158 SCV000279186 uncertain significance not provided 2016-07-12 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1040C>G at the cDNA level, p.Ala347Gly (A347G) at the protein level, and results in the change of an Alanine to a Glycine (GCG>GGG). This variant has been reported at least once, in an individual with breast cancer who underwent hereditary cancer panel testing (Tung 2016). STK11 Ala347Gly 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 Alanine and Glycine share similar properties, this is considered a conservative amino acid substitution. STK11 Ala347Gly occurs at a position that is not conserved and is located in the C-terminal domain (Hearle 2006). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether STK11 Ala347Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000527203 SCV000629056 uncertain significance Peutz-Jeghers syndrome 2018-08-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 347 of the STK11 protein (p.Ala347Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 141851). 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 glycine 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.

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