19-1218442-C-T

Position:

• chr19-1218442-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The ENST00000585748(STK11):​c.-57C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000273 in 1,613,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: STK11 ENST00000585748 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10 O:1
• Conservation: PhyloP100: 4.57

Genes affected

STK11 (HGNC:11389): (serine/threonine kinase 11) The protein encoded by this gene is a serine/threonine kinase that regulates cell polarity and energy metabolism and functions as a tumor suppressor. Mutations in this gene have been associated with the autosomal dominant Peutz-Jeghers syndrome, as well as with skin, pancreatic, and testicular cancers. [provided by RefSeq, May 2022]

STK11 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.316C>T	p.Arg106Trp	missense_variant	2/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.316C>T	p.Arg106Trp	missense_variant	2/9		NP_001394184.1
STK11	NR_176325.1	n.1583C>T		non_coding_transcript_exon_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000585748	c.-57C>T		5_prime_UTR_premature_start_codon_gain_variant	4/12	3		ENSP00000477641.2
STK11	ENST00000326873.12	c.316C>T	p.Arg106Trp	missense_variant	2/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.316C>T	p.Arg106Trp	missense_variant	2/9			ENSP00000498804.1
STK11	ENST00000585748	c.-57C>T		5_prime_UTR_variant	4/12	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.*141C>T		non_coding_transcript_exon_variant	3/4	3		ENSP00000466610.1
STK11	ENST00000593219.5	n.*141C>T		3_prime_UTR_variant	3/4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249164 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135212

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461276 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 726906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 106 of the STK11 protein (p.Arg106Trp). This variant is present in population databases (rs587782115, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 141922). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 25, 2024	This missense variant replaces arginine with tryptophan at codon 106 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 performed for this variant. This variant has been reported in an individual affected with breast cancer and neuroendocrine tumors (PMID: 31592449) although this individual also carries a truncating PALB2 variant. This variant has been identified in 3/280550 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. -

not provided Uncertain:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Uncertain significance and reported on 11-17-2020 by Lab or GTR ID 506138. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2024	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer and a neuroendocrine tumor who also harbored a pathogenic variant in PALB2 (PMID: 31592449); This variant is associated with the following publications: (PMID: 31469826, 36243179, 15863673, 31592449) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 18, 2023	In the published literature, this variant has been reported in an individual with breast cancer and neuroendocrine tumors that carries a pathogenic variant in the PALB2 gene (PMID: 31592449 (2019)). It has also been reported in unaffected individuals (PMID: 31469826 (2019)). The frequency of this variant in the general population, 0.000023 (3/128370 chromosomes in European (Non-Finnish) 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 26, 2024	The p.R106W variant (also known as c.316C>T), located in coding exon 2 of the STK11 gene, results from a C to T substitution at nucleotide position 316. The arginine at codon 106 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was reported in a patient with a small bowel neuroendocrine tumor; however, this individual was also was positive for a pathogenic mutation in the PALB2 gene as well as variants of unknown significance in the MLH1 and FANCM genes (Larouche V et al. Endocrinol Diabetes Metab, 2019 Oct;2:e00092). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 15, 2022	This missense variant replaces arginine with tryptophan at codon 106 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 performed for this variant. This variant has been reported in an individual affected with breast cancer and neuroendocrine tumors (PMID: 31592449) although this individual also carries a truncating PALB2 variant. This variant has been identified in 3/280550 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 21, 2023

Variant summary: STK11 c.316C>T (p.Arg106Trp) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249164 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.316C>T has been reported in the literature in an individual with concurrent breast cancer and small bowel neuroendocrine tumor (e.g., Larouche_2019), however without strong evidence for causality due to co-occurrence with a pathogenic variant (PALB2 c.3549C>A, p.Tyr1183X), providing supporting evidence for a benign role. This report therefore does 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. The following publications have been ascertained in the context of this evaluation (PMID: 31592449, 31383922). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

STK11-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2024

The STK11 c.316C>T variant is predicted to result in the amino acid substitution p.Arg106Trp. This variant was reported in an individual with concurrent breast cancer and neuroendocrine tumors; however, this individual also harbored additional variants in cancer-related genes including a pathogenic PALB2 variant (Patient 5, Larouche et al. 2019. PubMed ID: 31592449). This variant was also documented in unaffected controls but not affected individuals in a case-control study of pancreatic cancer (Dataset S1 and Table S2, Wong et al. 2019. PubMed ID: 31469826). This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141922/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.5	.;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0040	.;D
Sift4G	Uncertain	0.021	D;D
Polyphen		1.0	.;D
Vest4		0.58
MutPred		0.48		Loss of disorder (P = 0.0477);Loss of disorder (P = 0.0477);
MVP		0.71
MPC		2.1
ClinPred		0.98	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587782115; hg19: chr19-1218441;