Submissions for variant NM_000455.5(STK11):c.1069G>A (p.Glu357Lys)

gnomAD frequency: 0.00006  dbSNP: rs759473833

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000657031	SCV000232553	uncertain significance	not provided	2014-09-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000657031	SCV000279361	uncertain significance	not provided	2022-05-11	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 a germline pathogenic or benign variant to our knowledge; This variant is associated with the following publications: (PMID: 28642281)
Invitae	RCV000465950	SCV000541158	uncertain significance	Peutz-Jeghers syndrome	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 357 of the STK11 protein (p.Glu357Lys). 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: 198732). 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.
Ambry Genetics	RCV000563889	SCV000672331	likely benign	Hereditary cancer-predisposing syndrome	2023-12-22	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.
Color Diagnostics, LLC DBA Color Health	RCV000563889	SCV000910058	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 357 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 4/276478 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	RCV000780766	SCV000918290	uncertain significance	not specified	2022-10-10	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1069G>A (p.Glu357Lys) results in a 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 1.2e-05 in 245118 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1069G>A has been reported in the literature in an individual affected with Melanoma in settings of a 46-gene hotspot cancer panel assay allowing multiple gene testing from small diagnostic biopsies (example, Hamblin_2017). 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657031	SCV001469908	uncertain significance	not provided	2019-10-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000465950	SCV002057916	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000465950	SCV004818976	uncertain significance	Peutz-Jeghers syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 357 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 4/276478 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.