Submissions for variant NM_000455.5(STK11):c.1193C>T (p.Ala398Val)

gnomAD frequency: 0.00003  dbSNP: rs768058962

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163934	SCV000214530	likely benign	Hereditary cancer-predisposing syndrome	2020-08-24	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	RCV000234273	SCV000284849	uncertain significance	Peutz-Jeghers syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 398 of the STK11 protein (p.Ala398Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer and/or Lynch syndrome (PMID: 25980754, 26898890, 34326862). ClinVar contains an entry for this variant (Variation ID: 184646). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000657114	SCV000569242	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast and other cancers (Yurgelun et al., 2015; Caminsky et al., 2016); This variant is associated with the following publications: (PMID: 25980754, 26898890)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657114	SCV000602210	uncertain significance	not provided	2021-09-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000234273	SCV000784824	uncertain significance	Peutz-Jeghers syndrome	2017-01-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163934	SCV000902842	likely benign	Hereditary cancer-predisposing syndrome	2016-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000486365	SCV001363628	uncertain significance	not specified	2019-01-18	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1193C>T (p.Ala398Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 225196 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1193C>T has been reported in the literature in an individual affected with (suspected) Lynch syndrome (Yurgelun 2015) and in another individual with breast cancer (Caminsky 2016), however it was also found in 2/7325 European American women, who were older than 70 years of age, and never had cancer (in the FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262270	SCV001440079	uncertain significance	Breast carcinoma	2019-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000234273	SCV002057330	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163934	SCV002531655	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-01	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000234273	SCV002581461	uncertain significance	Peutz-Jeghers syndrome	2022-03-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000234273	SCV004017901	uncertain significance	Peutz-Jeghers syndrome	2023-04-12	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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000234273	SCV004041778	uncertain significance	Peutz-Jeghers syndrome	2023-10-09	no assertion criteria provided	clinical testing