Submissions for variant NM_000455.5(STK11):c.721G>A (p.Ala241Thr)

dbSNP: rs587780721

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123065	SCV000166360	uncertain significance	Peutz-Jeghers syndrome	2024-01-24	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 241 of the STK11 protein (p.Ala241Thr). 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 a Lynch syndrome-associated cancer and/or colon polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 135926). 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	RCV000161005	SCV000211715	uncertain significance	not provided	2021-08-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a history of Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015); This variant is associated with the following publications: (PMID: 25980754, 15863673)
Counsyl	RCV000123065	SCV000489281	uncertain significance	Peutz-Jeghers syndrome	2016-09-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580621	SCV000686677	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 241 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 2/241110 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.
Ambry Genetics	RCV000580621	SCV001188497	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-21	criteria provided, single submitter	clinical testing	The p.A241T variant (also known as c.721G>A), located in coding exon 5 of the STK11 gene, results from a G to A substitution at nucleotide position 721. The alanine at codon 241 is replaced by threonine, an amino acid with similar properties. This alteration was observed with an allele frequency of 0 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00009 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.00008 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant has been detected in multiple individuals with no reported features of STK11-associated disease (Ambry internal data). This amino acid position is highly conserved in available 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000161005	SCV001470105	uncertain significance	not provided	2019-11-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000161005	SCV001961751	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000123065	SCV002057835	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000123065	SCV004017993	uncertain significance	Peutz-Jeghers syndrome	2023-04-14	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.
Baylor Genetics	RCV003467088	SCV004205604	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 1	2022-10-11	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492540	SCV004239728	uncertain significance	Breast and/or ovarian cancer	2022-10-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000123065	SCV004818891	uncertain significance	Peutz-Jeghers syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 241 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 2/241110 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000161005	SCV002035087	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000161005	SCV002037087	uncertain significance	not provided		no assertion criteria provided	clinical testing