ClinVar Miner

Submissions for variant NM_000455.5(STK11):c.1062C>G (p.Phe354Leu) (rs59912467)

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Total submissions: 23
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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 2020-11-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115593 SCV000185922 benign Hereditary cancer-predisposing syndrome 2014-07-15 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Vantari Genetics RCV000115593 SCV000267092 benign Hereditary cancer-predisposing syndrome 2015-12-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115593 SCV000292116 benign Hereditary cancer-predisposing syndrome 2014-11-05 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000122091 SCV000304385 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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, Partners HealthCare 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 RCV001282655 SCV000605311 benign none provided 2020-07-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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
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
Human Genetics - Radboudumc,Radboudumc RCV000122091 SCV001957002 benign not specified no assertion criteria provided clinical testing

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