Submissions for variant NM_000455.5(STK11):c.1062C>G (p.Phe354Leu)

gnomAD frequency: 0.00348  dbSNP: rs59912467

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656543	SCV000149502	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20393878, 24604241, 22995991, 20722467, 25333069, 20981092, 24728327, 15121768, 25751324, 26182300, 22942091, 27153395, 24928005, 28185117, 30092773, 30334930, 33250696)
Invitae	RCV000007887	SCV000153890	benign	Peutz-Jeghers syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115593	SCV000185922	benign	Hereditary cancer-predisposing syndrome	2014-07-15	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Vantari Genetics	RCV000115593	SCV000267092	benign	Hereditary cancer-predisposing syndrome	2015-12-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115593	SCV000292116	benign	Hereditary cancer-predisposing syndrome	2014-11-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000122091	SCV000304385	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000007887	SCV000410747	benign	Peutz-Jeghers syndrome	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Counsyl	RCV000007887	SCV000488404	benign	Peutz-Jeghers syndrome	2016-03-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000122091	SCV000540465	benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 3.7% (283/7750) East Asian chromosomes; ClinVar: 3 benign, 1 VUS
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656543	SCV000605311	benign	not provided	2023-05-10	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000122091	SCV000700379	benign	not specified	2017-02-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115593	SCV000747824	likely benign	Hereditary cancer-predisposing syndrome	2018-01-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001797996	SCV002042760	benign	Breast and/or ovarian cancer	2019-05-06	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000007887	SCV002057454	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115593	SCV002531629	benign	Hereditary cancer-predisposing syndrome	2020-06-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000122091	SCV002552030	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504766	SCV002798542	likely benign	Carcinoma of pancreas; Peutz-Jeghers syndrome; Melanoma, cutaneous malignant, susceptibility to, 1; Germ cell tumor of testis	2021-10-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656543	SCV003918029	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	STK11: BS1, BS2
Myriad Genetics, Inc.	RCV000007887	SCV004017982	benign	Peutz-Jeghers syndrome	2023-04-14	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
OMIM	RCV000007887	SCV000028092	uncertain significance	Peutz-Jeghers syndrome	2005-05-15	no assertion criteria provided	literature only
ITMI	RCV000122091	SCV000086306	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000007887	SCV000189992	uncertain significance	Peutz-Jeghers syndrome	2014-07-24	no assertion criteria provided	clinical testing
Foundation Medicine, Inc.	RCV000122091	SCV000299350	uncertain significance	not specified		no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656543	SCV000692055	benign	not provided	2018-01-24	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000115593	SCV000788216	likely benign	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355263	SCV001550094	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The STK11 p.Phe354Leu variant was identified in 20 of 1472 proband chromosomes (frequency: 0.014) from Korean, Japanese, Chinese and American individuals or families with Peutz-Jeghers disease, and Finnish, Korean, (French) Canadian, Portuguese, Italian, American individuals with CRC, high risk breast cancer, hereditary diffuse gastric cancer, pancreatic cancer, and medullary thyroid cancer; and was identified in 5 of 824 control chromosomes (frequency: 0.006) from healthy individuals (Yang 2010, Yajima 2013, Liu 2012, Huang 2015, Amos 2003, Launonen 2000, Guenard 2010, Hansford 2015, Jordan 2016, Simbolo 2014 ). Segregation of the variant with disease was not seen in 2 healthy family members of the PJ affected proband (Liu 2012), or an affected (breast cancer) family member of another proband (Guenard 2010). In a case report of a 76 year old female with papillary thyroid cancer with no clinical manifestations of PJ, the variant was identified to co-occur with a BRAF mutation (p.V600E, c.1799T>A) in the tumour (Shuanzeng 2016). In another study, the variant was identified in 2 Chinese patients with sporadic PJS, co-occurring with separate pathogenic STK11 mutations (del(exon1) and c.890G > A) (Tan 2017). Functional assays of the STK11 exons 8 and 9, localized to the C-terminal non-catalytic region, have shown that mutations within this region neither disrupt STK11 activity nor interfere with STK11 induced growth arrest, but do lessen STK11-mediated activation of the AMP-activated protein kinase (AMPK) and downstream signaling (Forcet 2005). The variant was also identified in dbSNP (ID: rs59912467) “With Likely benign, other allele”, Clinvar (classified as conflicting interpretations of pathogenicity: benign by GeneDx, Invitae, Ambry Genetics, Prevention Genetics, Counsyl, Laboratory for Molecular Medicine (Partners for HealthCare Personalized Medicine), Vantari Genetics, Color Genomics Inc; likely benign by Illumina; uncertain significance by Foundation Medicine Inc, OMIM, Pathway Genomics; and unclassified by ITMI), Clinvitae (4X), Cosmic 41X in tumours of the brain, breast, lung, large intestine, salivary gland and malignant melanoma), LOVD 3.0 (3X), Zhejiang Colon Cancer database (11X, all in combination with other multiple STK11 variants, including pathogenic variants: c.842delC, p.Pro281ArgfsX6/c.996G>A, p.Trp332X/c.465-1G>T); and was not identified in the Insight Hereditary Tumors Database. The variant was identified in control databases in 1363 (17 homozygous) of 273698 chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following population at a frequency greater than 1%: East Asian in 658 (15 homozygous) of 18796 chromosomes (freq: 0.035). The p.Phe354 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000122091	SCV001741179	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000122091	SCV001808614	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000122091	SCV001922872	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000122091	SCV001957002	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000122091	SCV001973963	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000122091	SCV002034303	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000656543	SCV002036095	likely benign	not provided		no assertion criteria provided	clinical testing