Submissions for variant NM_000455.5(STK11):c.991C>T (p.Arg331Trp)

gnomAD frequency: 0.00001  dbSNP: rs876658594

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217573	SCV000274060	likely benign	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	RCV000460876	SCV000541169	uncertain significance	Peutz-Jeghers syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 331 of the STK11 protein (p.Arg331Trp). 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 colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 230490). 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.
Color Diagnostics, LLC DBA Color Health	RCV000217573	SCV000903692	uncertain significance	Hereditary cancer-predisposing syndrome	2018-11-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293583	SCV001482195	uncertain significance	not specified	2021-02-25	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.991C>T (p.Arg331Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-06 in 230396 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.991C>T has been reported in the literature in individuals affected with colorectal cancer and non-small cell lung cancer (Yurgelun_2017, Fumagalli_2019, Blons_2020). 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. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000460876	SCV002057894	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477719	SCV004221297	uncertain significance	not provided	2023-08-02	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with non-small cell lung cancer (PMID: 30669267 (2019)) and colorectal cancer (PMID: 28135145 (2017)). The frequency of this variant in the general population, 0.0000087 (2/230396 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000460876	SCV004818953	uncertain significance	Peutz-Jeghers syndrome	2023-06-28	criteria provided, single submitter	clinical testing