ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1108+3G>A (rs755746417)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561129 SCV000664353 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000561129 SCV000691471 likely benign Hereditary cancer-predisposing syndrome 2017-08-20 criteria provided, single submitter clinical testing
GeneDx RCV000445130 SCV000532358 likely benign not specified 2018-02-14 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000445130 SCV000918288 uncertain significance not specified 2018-06-04 criteria provided, single submitter clinical testing Variant summary: STK11 c.1108+3G>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.1e-05 in 237544 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1108+3G>A in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (3x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000230024 SCV000284842 uncertain significance Peutz-Jeghers syndrome 2018-12-08 criteria provided, single submitter clinical testing This sequence change falls in intron 8 of the STK11 gene. It does not directly change the encoded amino acid sequence of the STK11 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs755746417, ExAC 0.002%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 237787). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000445130 SCV000602206 likely benign not specified 2017-07-12 criteria provided, single submitter clinical testing

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