Submissions for variant NM_000455.5(STK11):c.614C>T (p.Ala205Val)

gnomAD frequency: 0.00001  dbSNP: rs587782468

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131568	SCV000186572	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	The p.A205V variant (also known as c.614C>T) is located in coding exon 5 of the STK11 gene. This alteration results from a C to T substitution at nucleotide position 614. The alanine at codon 205 is replaced by valine, an amino acid with similar properties. This residue is located in the activation loop of the catalytic kinase domain, and functional analyses of a different alteration at this position, p.A205T, demonstrated that p.A205T leads to the loss of cell growth inhibition in a head and neck squamous cell carcinoma cell line and disrupts kinase activity of the STK11 protein (Qiu W et al. Oncogene. 2006 May;25:2937-42). An additional study of p.A205T found that although the alanine at codon 205 acts as a molecular peg orienting the activation loop of STK11, this alteration does not affect the ability of STK11 to assemble into active complexes, and the authors suggested that it may be involved in interacting with other regulators of the STK11 pathway (Zeqiraj E et al. Science. 2009 Dec;326:1707-11). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species, although in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000168319	SCV000219004	uncertain significance	Peutz-Jeghers syndrome	2022-09-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 205 of the STK11 protein (p.Ala205Val). 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 variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 142443). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STK11 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.
Counsyl	RCV000168319	SCV000487863	uncertain significance	Peutz-Jeghers syndrome	2015-11-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000486177	SCV000566571	uncertain significance	not provided	2023-07-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as germline pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19892943, 26154128, 26010451, 15863673)
Color Diagnostics, LLC DBA Color Health	RCV000131568	SCV000686670	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 205 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 been identified in 4/209296 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	RCV000168319	SCV002057815	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131568	SCV002531717	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-23	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV000168319	SCV002549856	uncertain significance	Peutz-Jeghers syndrome	2022-07-08	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM2_SUP, PP3
Myriad Genetics, Inc.	RCV000168319	SCV004018024	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	RCV000168319	SCV004816387	uncertain significance	Peutz-Jeghers syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 205 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 been identified in 4/209296 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	RCV004586563	SCV005077246	likely benign	not specified	2024-04-18	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.614C>T (p.Ala205Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.6e-05 in 1590130 control chromosomes (gnomAD v4.0.0). The observed variant frequency is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.614C>T in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 142443). Based on the evidence outlined above, the variant was classified as likely benign.