Submissions for variant NM_000455.5(STK11):c.842C>T (p.Pro281Leu)

gnomAD frequency: 0.00006  dbSNP: rs121913322

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130951	SCV000185865	likely benign	Hereditary cancer-predisposing syndrome	2018-12-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV001719902	SCV000211716	likely benign	not provided	2021-02-15	criteria provided, single submitter	clinical testing	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: 9731485, 14687797, 27751357, 25343854, 17711506, 22723903, 10429654, 18594528, 10676634, 26185002, 21191700, 24857785, 26164066, 19892943, 29338689)
Invitae	RCV000232126	SCV000284877	likely benign	Peutz-Jeghers syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001719902	SCV000602238	benign	not provided	2022-12-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235215	SCV000696727	benign	not specified	2020-02-07	criteria provided, single submitter	clinical testing	STK11 c.842C>T (p.Pro281Leu) results in a non-conservative amino acid change located in the Catalytic domain of 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 0.00012 in 240870 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 240 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The c.842C>T variant has been reported in the literature in sequencing studies of individuals affected with multiple types of cancers (lung, colon, salivary gland, etc) without confirmation as a germline variant and also in one individual with pancreatic ductal adenocarcinoma as a germline variant (example, Ku_2014, Preusser_2015, Han_2014, Koivunen_2008, Onozato_2007, Jeong_2017, Ohmoto_2016). Additionally a recent Japanese case control association study on 7,051 unselected breast cancer cases and 11,241 female controls showed no association of this variant with breast cancer along with a final assessment as benign (Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome or HBOC. At-least two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (example, Zeqiraj_2009, Launonen_2000). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=1; likely benign, n=2; VUS, n=4). Based on the evidence outlined above, the variant was re-classified as benign.
Counsyl	RCV000232126	SCV000784770	uncertain significance	Peutz-Jeghers syndrome	2017-05-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000232126	SCV000839417	benign	Peutz-Jeghers syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130951	SCV000902811	benign	Hereditary cancer-predisposing syndrome	2020-12-10	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030733	SCV001193749	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Genome-Nilou Lab	RCV000232126	SCV002057287	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130951	SCV002526948	likely benign	Hereditary cancer-predisposing syndrome	2021-02-06	criteria provided, single submitter	curation
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153424	SCV003843433	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000232126	SCV004017998	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.
Database of Curated Mutations (DoCM)	RCV000419015	SCV000505695	likely pathogenic	Neoplasm	2015-07-14	no assertion criteria provided	literature only