ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1283C>G (p.Ser428Trp) (rs587781537)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129543 SCV000184323 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000657082 SCV000279601 uncertain significance not provided 2018-02-13 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1283C>G at the cDNA level, p.Ser428Trp (S428W) at the protein level, and results in the change of a Serine to a Tryptophan (TCG>TGG). This variant was observed in at least one individual with a Lynch syndrome-associated cancer and/or colon polyps (Yurgelun 2015). STK11 Ser428Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). STK11 Ser428Trp is located within the c-terminal domain (Hearle 2006). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether STK11 Ser428Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000216446 SCV000602214 uncertain significance not specified 2017-07-25 criteria provided, single submitter clinical testing
Invitae RCV000549140 SCV000629092 uncertain significance Peutz-Jeghers syndrome 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces serine with tryptophan at codon 428 of the STK11 protein (p.Ser428Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. The frequency data for this variant (rs587781537) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported in an individual with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 141156). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this sequence change is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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.
Color RCV000129543 SCV000686615 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing

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