Submissions for variant NM_000455.5(STK11):c.1127A>C (p.Glu376Ala)

gnomAD frequency: 0.00007  dbSNP: rs373888280

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586344	SCV000149503	uncertain significance	not provided	2021-05-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a pediatric patient diagnosed with an unspecified cancer (Chan 2018); This variant is associated with the following publications: (PMID: 30455982)
Ambry Genetics	RCV000115594	SCV000184985	likely benign	Hereditary cancer-predisposing syndrome	2022-01-12	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	RCV000205503	SCV000260042	likely benign	Peutz-Jeghers syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115594	SCV000686590	likely benign	Hereditary cancer-predisposing syndrome	2021-10-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855606	SCV000696702	uncertain significance	not specified	2024-03-24	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1127A>C (p.Glu376Ala) 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 2.1e-05 in 241804 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1127A>C has been reported in the literature as a VUS in at-least one individual within a cohort of children with malignant pediatric tumors (example, Chan _2018). 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. The following publication have been ascertained in the context of this evaluation (PMID: 30455982). ClinVar contains an entry for this variant (Variation ID: 127698). Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000205503	SCV000785631	uncertain significance	Peutz-Jeghers syndrome	2017-10-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000205503	SCV002057933	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115594	SCV002531640	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000205503	SCV004018006	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586344	SCV004221265	uncertain significance	not provided	2023-01-05	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00026 (6/23256 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant was identified in a cohort of children affected with various solid tumors (PMID: 30455982 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492475	SCV004239715	uncertain significance	Breast and/or ovarian cancer	2022-09-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115594	SCV002050283	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-23	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000205503	SCV004228902	not provided	Peutz-Jeghers syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-09-2020 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.