ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463079 SCV000541132 pathogenic Peutz-Jeghers syndrome 2018-12-25 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 Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
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.

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