Submissions for variant NM_000455.5(STK11):c.31A>G (p.Met11Val)

dbSNP: rs753834428

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222194	SCV000278097	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-29	criteria provided, single submitter	clinical testing	The p.M11V variant (also known as c.31A>G), located in coding exon 1 of the STK11 gene, results from an A to G substitution at nucleotide position 31. The methionine at codon 11 is replaced by valine, an amino acid with highly similar properties. In one study, this variant was reported in 1/1824 patients with triple negative breast cancer unselected for family history of breast or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11). This alteration has also been reported in an individual affected with colorectal cancer (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232648	SCV000284863	uncertain significance	Peutz-Jeghers syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 11 of the STK11 protein (p.Met11Val). This variant is present in population databases (rs753834428, gnomAD 0.001%). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 233673). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000485960	SCV000572439	uncertain significance	not provided	2024-09-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25452441, 36243179, 28944238)
Color Diagnostics, LLC DBA Color Health	RCV000222194	SCV001356959	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 11 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with triple negative breast cancer (PMID: 25452441) and an individual affected with colorectal cancer (PMID: 28944238). This variant has not been identified 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	RCV000232648	SCV002057713	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462529	SCV004205565	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 1	2023-08-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000232648	SCV004816298	uncertain significance	Peutz-Jeghers syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with valine at codon 11 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in one individual affected with triple negative breast cancer in the literature (PMID: 25452441). This variant has not been identified 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.