Submissions for variant NM_000455.5(STK11):c.632G>A (p.Arg211Gln)

gnomAD frequency: 0.00001  dbSNP: rs730881982

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235214	SCV000211714	uncertain significance	not provided	2021-08-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Tung 2015); This variant is associated with the following publications: (PMID: 15863673, 25186627)
Ambry Genetics	RCV000161004	SCV000213934	likely benign	Hereditary cancer-predisposing syndrome	2021-07-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000196911	SCV000254555	likely benign	Peutz-Jeghers syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000196911	SCV000786304	uncertain significance	Peutz-Jeghers syndrome	2018-04-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765432	SCV000896716	uncertain significance	Carcinoma of pancreas; Peutz-Jeghers syndrome; Malignant tumor of testis	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000161004	SCV000903623	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 211 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 breast cancer in the literature (PMID: 25186627, 33471991). This variant has been identified in 10/223198 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	RCV000781892	SCV000920278	likely benign	not specified	2021-10-15	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.632G>A (p.Arg211Gln) results in a conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 223198 control chromosomes (gnomAD v2.1 exomes dataset). The observed variant frequency is approximately 7-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. The variant, c.632G>A, has been reported in the literature in 3 individuals affected breast cancer (Tung_2015, Dorling_2021). These reports however, 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. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000196911	SCV001440078	uncertain significance	Peutz-Jeghers syndrome	2019-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000196911	SCV002057273	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000781892	SCV002071119	uncertain significance	not specified	2019-08-30	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149983	SCV003837868	uncertain significance	Breast and/or ovarian cancer	2021-12-13	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000196911	SCV004017960	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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000196911	SCV004041673	uncertain significance	Peutz-Jeghers syndrome	2023-10-09	no assertion criteria provided	clinical testing