Submissions for variant NM_000455.5(STK11):c.1276C>T (p.Arg426Trp)

gnomAD frequency: 0.00001  dbSNP: rs587782687

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163116	SCV000213627	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	The p.R426W variant (also known as c.1276C>T), located in coding exon 9 of the STK11 gene, results from a C to T substitution at nucleotide position 1276. The arginine at codon 426 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in 2 individuals with gastrointestinal polyps of multiple pathologic types; however, neither individual had been found with classic PJS-type hamartomatous polyps (Ngeow J, Gastroenterology 2013 Jun; 144(7):1402-9, 1409.e1-5). This variant has been detected in multiple individuals with no reported features of Peutz-Jeghers syndrome (Ambry internal data) 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	RCV000168123	SCV000218780	uncertain significance	Peutz-Jeghers syndrome	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 426 of the STK11 protein (p.Arg426Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with colorectal polyps, breast cancer, and biliary tract cancer (PMID: 23399955, 30287823, 36243179). ClinVar contains an entry for this variant (Variation ID: 184011). 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.
Counsyl	RCV000168123	SCV000488069	uncertain significance	Peutz-Jeghers syndrome	2015-12-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163116	SCV000686613	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan 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 been reported in individuals affected with gastrointestinal polyps (PMID: 23399955) and breast cancer (PMID: 30287823, Poster: Lee et al. 2018, ESMO Asia 2018). This variant has also been reported in control individuals (PMID: 30287823). This variant has been identified in 2/145682 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194241	SCV001363624	uncertain significance	not specified	2019-01-14	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1276C>T (p.Arg426Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7e-06 in 143356 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1276C>T has been reported in the literature in individuals affected with gasterointestinal polyposis, and malignant solid tumors such as lung cancer and mixed ductal endocrine cancer (Kim_2010, Ngeow_2013, Tanabe_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000168123	SCV002058008	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002298489	SCV002588067	uncertain significance	not provided	2022-10-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28900777, 27852271, 23399955, 20082862, 30287823)
Myriad Genetics, Inc.	RCV000168123	SCV004017965	uncertain significance	Peutz-Jeghers syndrome	2023-04-13	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	RCV000168123	SCV004819031	uncertain significance	Peutz-Jeghers syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan 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 been reported in individuals affected with gastrointestinal polyps (PMID: 23399955) and breast cancer (PMID: 30287823, Poster: Lee et al. 2018, ESMO Asia 2018). This variant has also been reported in control individuals (PMID: 30287823). This variant has been identified in 2/145682 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.