Submissions for variant NM_000455.5(STK11):c.827G>T (p.Gly276Val)

gnomAD frequency: 0.00004  dbSNP: rs749927908

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000459041	SCV000541163	likely benign	Peutz-Jeghers syndrome	2024-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000487182	SCV000567908	uncertain significance	not provided	2019-07-22	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: 28069802, 28640387)
Ambry Genetics	RCV000572801	SCV000664361	benign	Hereditary cancer-predisposing syndrome	2022-10-17	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.
Color Diagnostics, LLC DBA Color Health	RCV000572801	SCV000910048	likely benign	Hereditary cancer-predisposing syndrome	2020-03-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260426	SCV001437422	uncertain significance	not specified	2020-09-14	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.827G>T (p.Gly276Val) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) 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 2.5e-05 in 243178 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.827G>T has been reported in the literature in at least one individual affected with colorectal cancer (Ricker_2017). This report does not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. Co-occurrence with another pathogenic variant has been reported in the literature (MLH1 c.1852_1854delAAG, p.Lys618del; Ricker_2017), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000459041	SCV002057285	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000572801	SCV002526943	likely benign	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000487182	SCV002774743	uncertain significance	not provided	2021-07-21	criteria provided, single submitter	clinical testing