Submissions for variant NM_000455.5(STK11):c.597+8C>T

gnomAD frequency: 0.00017  dbSNP: rs565387911

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213014	SCV000171887	benign	not specified	2014-04-01	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000131656	SCV000186683	likely benign	Hereditary cancer-predisposing syndrome	2013-05-22	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.
Invitae	RCV000457082	SCV000554150	benign	Peutz-Jeghers syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477535	SCV000602231	benign	not provided	2022-10-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131656	SCV000686667	likely benign	Hereditary cancer-predisposing syndrome	2016-01-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000213014	SCV001519525	benign	not specified	2021-03-07	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.597+8C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 221274 control chromosomes. The observed variant frequency is approximately 20 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 benign. To our knowledge, no occurrence of c.597+8C>T in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.6468_6469delTC, p.Q2157fs), providing supporting evidence for a benign role. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=1)/likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV000457082	SCV002057417	likely benign	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003915280	SCV004728947	likely benign	STK11-related disorder	2019-05-14	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).