ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1190C>T (p.Ala397Val) (rs558040549)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129317 SCV000184080 likely benign Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000656984 SCV000211726 uncertain significance not provided 2014-09-09 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1190C>T at the cDNA level, p.Ala397Val (A397V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Ala397Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. STK11 Ala397Val occurs at a position that is variable across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether STK11 Ala397Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000205254 SCV000259688 likely benign Peutz-Jeghers syndrome 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000205254 SCV000488093 uncertain significance Peutz-Jeghers syndrome 2015-12-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213033 SCV000602209 uncertain significance not specified 2017-03-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129317 SCV000911237 likely benign Hereditary cancer-predisposing syndrome 2016-10-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000213033 SCV001448585 likely benign not specified 2020-11-06 criteria provided, single submitter clinical testing Variant summary: STK11 c.1190C>T (p.Ala397Val) results in a non-conservative amino acid change in 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 7.4e-05 in 231272 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 12 fold of 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. In addition, the variant was also found in healthy Japanese population at a frequency of 0.0004 (jMorp database, 4.7K healthy Japanese individuals). c.1190C>T has been reported in the literature (e.g. Kim_2019). These reports, however do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.

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