ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1036G>A (p.Gly346Ser) (rs375431906)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130584 SCV000185456 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000206247 SCV000260018 uncertain significance Peutz-Jeghers syndrome 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 346 of the STK11 protein (p.Gly346Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs375431906, ExAC 0.01%) but has not been reported in the literature in individuals with an STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 141886). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000482308 SCV000570331 uncertain significance not specified 2017-04-21 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1036G>A at the cDNA level, p.Gly346Ser (G346S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Gly346Ser was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Gly346Ser occurs at a position that is conserved across species and is located in the c-terminal domain (Hearle 2006). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether STK11 Gly346Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130584 SCV000686577 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-10 criteria provided, single submitter clinical testing

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