Submissions for variant NM_000455.5(STK11):c.1180G>A (p.Gly394Ser)

dbSNP: rs768780695

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163162	SCV000213680	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-17	criteria provided, single submitter	clinical testing	The p.G394S variant (also known as c.1180G>A), located in coding exon 9 of the STK11 gene, results from a G to A substitution at nucleotide position 1180. The glycine at codon 394 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the 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	RCV000168138	SCV000218798	uncertain significance	Peutz-Jeghers syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 394 of the STK11 protein (p.Gly394Ser). This variant is present in population databases (rs768780695, gnomAD 0.003%). 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: 184046). 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	RCV000168138	SCV000489396	uncertain significance	Peutz-Jeghers syndrome	2016-09-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163162	SCV000686601	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-06	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 394 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 hereditary cancer in the literature. This variant has been identified in 4/236716 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.
Mendelics	RCV000168138	SCV000839430	uncertain significance	Peutz-Jeghers syndrome	2018-07-02	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761079	SCV000890994	uncertain significance	Embryonal rhabdomyosarcoma	2017-06-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264531	SCV001442735	uncertain significance	not specified	2020-10-29	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1180G>A (p.Gly394Ser) 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 1.7e-05 in 236716 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1180G>A in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001808435	SCV002056073	uncertain significance	not provided	2022-07-20	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33528079)
Genome-Nilou Lab	RCV000168138	SCV002057960	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002485009	SCV002788230	uncertain significance	Carcinoma of pancreas; Peutz-Jeghers syndrome; Melanoma, cutaneous malignant, susceptibility to, 1; Germ cell tumor of testis	2022-05-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000168138	SCV004017918	uncertain significance	Peutz-Jeghers syndrome	2023-04-12	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001808435	SCV004224519	uncertain significance	not provided	2023-02-08	criteria provided, single submitter	clinical testing	PM2