ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1254C>G (p.Cys418Trp) (rs587780715)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131151 SCV000186093 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient or conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000123057 SCV000503556 uncertain significance Peutz-Jeghers syndrome 2016-08-01 no assertion criteria provided research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 47 year old with a history of colon cancer diagnosed at 47 and a family history of colon cancer.
Color RCV000131151 SCV000686608 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing
Counsyl RCV000123057 SCV000487848 uncertain significance Peutz-Jeghers syndrome 2015-11-21 criteria provided, single submitter clinical testing
GeneDx RCV000585976 SCV000211729 uncertain significance not provided 2018-12-31 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1254C>G at the cDNA level, p.Cys418Trp (C418W) at the protein level, and results in the change of a Cysteine to a Tryptophan (TGC>TGG). This variant was observed in at least one individual referred for hereditary cancer testing (Shirts 2016). STK11 Cys418Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). STK11 Cys418Trp is located within the C-terminal region (Daniell 2017). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether STK11 Cys418Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000585976 SCV000696708 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing Variant summary: The STK11 c.1254C>G (p.Cys418Trp) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 21920 control chromosomes. The variant has been reported once in the literature, to our knowledge, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000123057 SCV000166352 uncertain significance Peutz-Jeghers syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tryptophan at codon 418 of the STK11 protein (p.Cys418Trp). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and tryptophan. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 135918). 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000131151 SCV000266231 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing

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