Submissions for variant NM_000455.5(STK11):c.407T>C (p.Met136Thr)

dbSNP: rs1060499958

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463079	SCV000541132	pathogenic	Peutz-Jeghers syndrome	2022-06-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STK11 protein function. ClinVar contains an entry for this variant (Variation ID: 403772). This missense change has been observed in individuals with clinical features of Peutz-Jeghers syndrome (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 136 of the STK11 protein (p.Met136Thr).
Ambry Genetics	RCV000492630	SCV000580924	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-07-03	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. This variant has been observed in multiple individuals with a personal and/or family history that is consistent with Peutz-Jeghers syndrome (External communication, Ambry internal data). Based on internal structural analysis, M136T is mildly destabilizing to the local structure and more destabilizing than a nearby pathogenic variant (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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.
Genome-Nilou Lab	RCV000463079	SCV002057241	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing