Submissions for variant NM_000455.5(STK11):c.1012G>A (p.Val338Met)

gnomAD frequency: 0.00001  dbSNP: rs587782302

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131186	SCV000186135	likely benign	Hereditary cancer-predisposing syndrome	2022-01-04	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	RCV000168376	SCV000219067	uncertain significance	Peutz-Jeghers syndrome	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 338 of the STK11 protein (p.Val338Met). This variant is present in population databases (rs587782302, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 142198). 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.
GeneDx	RCV000222337	SCV000279260	likely benign	not provided	2019-08-19	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28135145)
Counsyl	RCV000168376	SCV000489083	uncertain significance	Peutz-Jeghers syndrome	2016-08-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131186	SCV000686573	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 338 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 an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 5/238888 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000222337	SCV000888633	uncertain significance	not provided	2017-09-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765433	SCV000896717	uncertain significance	Carcinoma of pancreas; Peutz-Jeghers syndrome; Malignant tumor of testis	2018-10-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000168376	SCV002057304	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002243796	SCV002512235	uncertain significance	Familial adenomatous polyposis 2	2021-09-26	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderate, BP4 supporting
Sema4, Sema4	RCV000131186	SCV002531617	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-19	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000168376	SCV004017986	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.
PreventionGenetics, part of Exact Sciences	RCV003407552	SCV004116326	uncertain significance	STK11-related disorder	2023-05-25	criteria provided, single submitter	clinical testing	The STK11 c.1012G>A variant is predicted to result in the amino acid substitution p.Val338Met. This variant has been reported in an individual with colorectal cancer (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). This variant is reported in 0.020% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-1223075-G-A). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/142198/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000168376	SCV004818955	uncertain significance	Peutz-Jeghers syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 338 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 an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 5/238888 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354464	SCV001549089	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli		no assertion criteria provided	clinical testing	The STK11 p.Val338Met variant was identified in 1 of 2116 proband chromosomes (frequency: 0.0005) from individuals or families with colorectal cancer (Yurgelun 2017). The variant was also identified in dbSNP (ID: rs587782302) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, Counsyl and Color). The variant was not identified in LOVD 3.0, database. The variant was identified in control databases in 4 of 236508 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 107242 chromosomes (freq: 0.00002), Ashkenazi Jewish in 2 of 9626 chromosomes (freq: 0.0002), while the variant was not observed in the African, Other, Latino, East Asian, Finnish, or South Asian populations. The p.Val338 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.