Submissions for variant NM_000455.5(STK11):c.1217C>T (p.Ala406Val)

gnomAD frequency: 0.00001  dbSNP: rs748202003

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204370	SCV000261236	likely benign	Peutz-Jeghers syndrome	2024-01-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000222032	SCV000279465	uncertain significance	not provided	2022-07-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer in published literature (Chan et al., 2018); This variant is associated with the following publications: (PMID: 28900777, 30093976)
Counsyl	RCV000204370	SCV000489233	uncertain significance	Peutz-Jeghers syndrome	2016-09-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565860	SCV000664325	likely benign	Hereditary cancer-predisposing syndrome	2023-01-11	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	RCV000565860	SCV000911545	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-04	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 406 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 and or ovarian cancer (PMID: 27153395, 30093976, 32720237). This variant has been identified in 7/236552 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	RCV001192852	SCV001361274	uncertain significance	not specified	2019-05-23	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1217C>T (p.Ala406Val) results in a non-conservative amino acid change in 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 2.9e-05 in 205184 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1217C>T, has been reported in the literature in individuals affected with breast cancer (Chan_2018). The report does 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. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant five times as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000204370	SCV002057975	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000565860	SCV002531660	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-22	criteria provided, single submitter	curation
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153487	SCV003843401	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000204370	SCV004017898	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000222032	SCV004221267	uncertain significance	not provided	2023-07-18	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with breast cancer (PMID: 30093976 (2018)). The frequency of this variant in the general population, 0.00018 (3/16680 chromosomes in East Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001192852	SCV004242954	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000204370	SCV004819012	uncertain significance	Peutz-Jeghers syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 406 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 and or ovarian cancer in the literature (PMID: 27153395, 30093976). This variant has been identified in 7/236552 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.