Submissions for variant NM_000455.5(STK11):c.1226G>A (p.Arg409Gln)

gnomAD frequency: 0.00003  dbSNP: rs587782364

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131326	SCV000186299	likely benign	Hereditary cancer-predisposing syndrome	2018-04-30	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.
Invitae	RCV000197480	SCV000254544	uncertain significance	Peutz-Jeghers syndrome	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 409 of the STK11 protein (p.Arg409Gln). 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 breast cancer, uterine cancer and sarcoma (PMID: 30287823, 34326862). ClinVar contains an entry for this variant (Variation ID: 142292). 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	RCV000197480	SCV000488336	uncertain significance	Peutz-Jeghers syndrome	2016-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000657038	SCV000567098	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	Observed in breast cancer cases and also in unaffected controls (Momozawa et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28900777, 30287823)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000487216	SCV000602212	uncertain significance	not specified	2017-06-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131326	SCV000686606	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 409 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 7/193536 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000487216	SCV000731470	uncertain significance	not specified	2017-04-21	criteria provided, single submitter	clinical testing	The p.Arg409Gln variant in STK11 has not been previously reported in the literat ure in individuals with Peutz-Jeghers syndrome, but has been reported in ClinVar (Variation ID 142292). This variant has also been identified in 6/80576 of Euro pean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broad institute.org; dbSNP rs587782364). Computational prediction tools and conservati on analysis suggest that the p.Arg409Gln variant may not impact the protein, tho ugh this information is not predictive enough to rule out pathogenicity. In summ ary, the clinical significance of the p.Arg409Gln variant is uncertain.
PreventionGenetics, part of Exact Sciences	RCV000657038	SCV000806072	uncertain significance	not provided	2018-01-09	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000197480	SCV002012396	uncertain significance	Peutz-Jeghers syndrome	2021-09-09	criteria provided, single submitter	clinical testing	The STK11 c.1226G>A (p.Arg409Gln) missense change has a maximum subpopulation frequency of 0.0060% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/19-1226570-G-A). This variant is reported 2x in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/variant/19-1226570-G-A). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), however these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Peutz-Jeghers syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Genome-Nilou Lab	RCV000197480	SCV002057335	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000487216	SCV002552041	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000197480	SCV004018008	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657038	SCV004563282	uncertain significance	not provided	2023-05-26	criteria provided, single submitter	clinical testing	The STK11 c.1226G>A; p.Arg409Gln variant (rs587782364) to our knowledge, is not reported in the medical literature in an STK11-related condition but has been reported in a healthy control (Momozawa 2018). This variant is also reported in ClinVar (Variation ID: 142292) and is found in the general population with an overall allele frequency of 0.0036% (7/193,536 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.167). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. PMID: 30287823.
All of Us Research Program, National Institutes of Health	RCV000197480	SCV004819015	uncertain significance	Peutz-Jeghers syndrome	2023-04-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 409 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 7/193536 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.
GenomeConnect - Invitae Patient Insights Network	RCV000197480	SCV004228742	not provided	Peutz-Jeghers syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-02-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.