Submissions for variant NM_000455.5(STK11):c.440G>A (p.Arg147His)

dbSNP: rs587780717

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123060	SCV000166355	uncertain significance	Peutz-Jeghers syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 147 of the STK11 protein (p.Arg147His). 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 personal or family history of breast and/or ovarian cancer (PMID: 34284872, 34326862). ClinVar contains an entry for this variant (Variation ID: 135921). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STK11 protein function. 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	RCV000216877	SCV000279177	uncertain significance	not provided	2020-07-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal history of sporadic breast cancer (Antov 2017)
Ambry Genetics	RCV000565548	SCV000664311	likely benign	Hereditary cancer-predisposing syndrome	2022-02-24	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.
Color Diagnostics, LLC DBA Color Health	RCV000565548	SCV000686648	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 147 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer in the literature (doi: 10.2298/GENSR1702399A). This variant has been identified in 5/218366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216877	SCV001469917	uncertain significance	not provided	2023-09-19	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMID: 34284872 (2022)), colorectal cancer (PMID: 34326862 (2021)), and pancreatic cancer (PMID: 35171259 (2022)). The frequency of this variant in the general population, 0.000023 (5/218366 chromosomes in total subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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.
Genome-Nilou Lab	RCV000123060	SCV002057792	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492539	SCV004239722	uncertain significance	Breast and/or ovarian cancer	2023-01-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123060	SCV004816359	uncertain significance	Peutz-Jeghers syndrome	2023-09-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 147 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer in the literature (doi: 10.2298/GENSR1702399A). This variant has been identified in 5/218366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.