ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.632G>A (p.Arg211Gln) (rs730881982)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235214 SCV000211714 uncertain significance not provided 2016-04-18 criteria provided, single submitter clinical testing This variant is denoted STK11 c.632G>A at the cDNA level, p.Arg211Gln (R211Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Arg211Gln 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 Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. STK11 Arg211Gln occurs at a position that is conserved across species and is located within the protein kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether STK11 Arg211Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000161004 SCV000213934 uncertain significance Hereditary cancer-predisposing syndrome 2014-11-12 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 RCV000196911 SCV000254555 uncertain significance Peutz-Jeghers syndrome 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 211 of the STK11 protein (p.Arg211Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs730881982, ExAC 0.02%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 182910). 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. 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.
Counsyl RCV000196911 SCV000786304 uncertain significance Peutz-Jeghers syndrome 2018-04-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765432 SCV000896716 uncertain significance Carcinoma of pancreas; Peutz-Jeghers syndrome; Malignant tumor of testis 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000161004 SCV000903623 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781892 SCV000920278 likely benign not specified 2018-03-30 criteria provided, single submitter clinical testing Variant summary: STK11 c.632G>A (p.Arg211Gln) results in a conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 219594 control chromosomes, which is approximately 7 fold above the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. c.632G>A has been reported in the literature in individuals affected with breast cancer (Tung_2014). However, these reports do not provide strong evidence about an association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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