Submissions for variant NM_000455.5(STK11):c.1276C>G (p.Arg426Gly)

dbSNP: rs587782687

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132118	SCV000187186	likely benign	Hereditary cancer-predisposing syndrome	2023-03-10	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.
Counsyl	RCV000410170	SCV000488871	uncertain significance	Peutz-Jeghers syndrome	2016-07-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000485540	SCV000570750	uncertain significance	not provided	2016-06-22	criteria provided, single submitter	clinical testing	This variant is denoted STK11 c.1276C>G at the cDNA level, p.Arg426Gly (R426G) at the protein level, and results in the change of an Arginine to a Glycine (CGG>GGG). This variant was observed in an individual with malignant pleural mesothelioma (Bueno 2016). STK11 Arg426Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Arg426Gly occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located within the C-terminal domain (Hearle 2006). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether STK11 Arg426Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000410170	SCV000629091	uncertain significance	Peutz-Jeghers syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 426 of the STK11 protein (p.Arg426Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 142743). 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 not expected to disrupt STK11 protein function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000132118	SCV001348640	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 426 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 reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. 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	RCV000410170	SCV002058009	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410170	SCV004018011	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.
Baylor Genetics	RCV003462033	SCV004205574	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 1	2023-07-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000410170	SCV004819029	uncertain significance	Peutz-Jeghers syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 426 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 reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. 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.