Submissions for variant NM_000455.5(STK11):c.1100C>T (p.Thr367Met)

gnomAD frequency: 0.00003  dbSNP: rs587782835

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132421	SCV000187513	likely benign	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000197228	SCV000254538	likely benign	Peutz-Jeghers syndrome	2024-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000222146	SCV000279187	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies are inconclusive: decrease in nucleus export efficiency and impairment of LKB1-mediated activation of the AMPK pathway with kinase activity, autophosphorylation, cellular localization, and colony formation similar to wild type (Launonen et al., 2000; Forcet et al., 2005); This variant is associated with the following publications: (PMID: 9731485, 14518068, 18774945, 26798439, 15800014, 10676634, 28900777)
Counsyl	RCV000197228	SCV000488509	uncertain significance	Peutz-Jeghers syndrome	2016-04-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132421	SCV001351983	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 367 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant retains STK11 auto-phosphorylation and growth arrest activities, but may be partially impaired for STK11-mediated activation of the AMPK pathway, nuclear export, and establishment and maintenance of cell polarity (PMID: 10676634, 15800014). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/273450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000197228	SCV002057924	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267886	SCV002552032	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000197228	SCV004018001	uncertain significance	Peutz-Jeghers syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV000197228	SCV004818981	uncertain significance	Peutz-Jeghers syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 367 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant retains STK11 auto-phosphorylation and growth arrest activities, but may be partially impaired for STK11-mediated activation of the AMPK pathway, nuclear export, and establishment and maintenance of cell polarity (PMID: 10676634, 15800014). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/273450 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.