Submissions for variant NM_000455.5(STK11):c.1258G>A (p.Ala420Thr)

dbSNP: rs762482152

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000226740	SCV000284855	uncertain significance	Peutz-Jeghers syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 420 of the STK11 protein (p.Ala420Thr). 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 ovarian cancer, who was suspected of having Peutz-Jeghers syndrome (PMID: 19145097). ClinVar contains an entry for this variant (Variation ID: 237794). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455443	SCV000540467	uncertain significance	not specified	2016-10-26	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in HGMD in a patient with Peutz-Jeghers (no access to paper). It is present in ExAC at a MaxMAF of 0.1% (1/948). AA is not conserved - 5 mammals and 15 non-mammals have a Thr at this position. Predicted to be benign by multiple prediction tools.
GeneDx	RCV000766974	SCV000568653	uncertain significance	not provided	2018-06-14	criteria provided, single submitter	clinical testing	This variant is denoted STK11 c.1258G>A at the cDNA level, p.Ala420Thr (A420T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant has been reported in an individual suspected of having Peutz-Jeghers syndrome (Heinritz 2008). STK11 Ala420Thr was not observed in large population cohorts (Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Ala420Thr is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether STK11 Ala420Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000569699	SCV000664306	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-02	criteria provided, single submitter	clinical testing	The p.A420T variant (also known as c.1258G>A), located in coding exon 9 of the STK11 gene, results from a G to A substitution at nucleotide position 1258. The alanine at codon 420 is replaced by threonine, an amino acid with similar properties. This variant was identified in a patient with cystic-papillary serous carcinoma of the ovary at age 28, slight perioral hyperpigmentation and facial freckling; however, she had no reported history of gastrointestinal problems, Peutz-Jeghers syndrome or cancer in her family (Heinritz W et al., Onkologie 2008 Nov; 31(11):625-8). This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000569699	SCV000911846	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-29	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 420 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 reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 19145097). This variant has also been identified in 2/162116 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	RCV000766974	SCV001134838	uncertain significance	not provided	2019-08-21	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000226740	SCV002057998	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000226740	SCV003818112	uncertain significance	Peutz-Jeghers syndrome	2019-03-04	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000455443	SCV004242955	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing