ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.407T>C (p.Met136Thr) (rs1060499958)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463079 SCV000541132 pathogenic Peutz-Jeghers syndrome 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 136 of the STK11 protein (p.Met136Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of Peutz-Jeghers syndrome, and shown to segregate with disease in two families (Invitae). ClinVar contains an entry for this variant (Variation ID: 403772). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000492630 SCV000580924 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-24 criteria provided, single submitter clinical testing The p.M136T variant (also known as c.407T>C), located in coding exon 3 of the STK11 gene, results from a T to C substitution at nucleotide position 407. The methionine at codon 136 is replaced by threonine, an amino acid with similar properties. While this exact variant has not been reported in the literature, two other alterations at the same codon (p.M136R and p.M136K), have been previously reported in individuals with Peutz-Jeghers syndrome (Olschwang S et al. J. Med. Genet. 2001 Jun; 38(6):356-60; Tchekmedyian A et al. PLoS ONE 2013;8(11):e79639). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6481 samples (12962 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 125000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000520340 SCV000618504 likely pathogenic not provided 2019-01-03 criteria provided, single submitter clinical testing The M136T variant in the STK11 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M136T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and is located within the site of catalysis (Hearle et al., 2006). In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (M136K, M136R) have been reported in association with Peutz-Jeghers syndrome, supporting the functional importance of this region of the protein (Olschwang et al., 2001; Tchekmedyian et al., 2013). Based on the currently available information, M136T is a strong candidate for a pathogenic variant. However, the possibility it may be a rare benign variant cannot be excluded.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001199886 SCV001370639 uncertain significance not specified 2020-05-26 criteria provided, single submitter clinical testing Variant summary: STK11 c.407T>C (p.Met136Thr) results in a non-conservative amino acid change located in the Protein Kinase Domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 225652 control chromosomes. 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.407T>C in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported in the literature. However, a clinical lab via ClinVar has reported the variant to occur in several individuals with clinical features of Peutz-Jeghers syndrome, and shown to segregate with disease in two families (Invitae), witout evidence to independently assess. Additionally, other variants at the same amino acid position have been reported in the literature in indivduals with PJS (M136K, M126R; Tchekmedyian_2013, Olschwang_2001). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, two classified as likely pathogenic/pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as VUS.

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