rs587782259

Positions:

• chr19-1226655-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000455.5(STK11):​c.*8C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000277 in 1,513,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: STK11 NM_000455.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:12
• Conservation: PhyloP100: -2.29

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-1226655-C-T is Benign according to our data. Variant chr19-1226655-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139340.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=7, Uncertain_significance=3}. Variant chr19-1226655-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000256 (39/152240) while in subpopulation AMR AF= 0.000458 (7/15294). AF 95% confidence interval is 0.000267. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.*8C>T		3_prime_UTR_variant	9/10	ENST00000326873.12
STK11	NR_176325.1	n.2577C>T		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.*8C>T		3_prime_UTR_variant	9/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.000382

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000304 AC: 34 AN: 112010 Hom.: 0 AF XY: 0.000258 AC XY: 16 AN XY: 62086

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.000606

Gnomad ASJ exome AF: 0.000158

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000470

Gnomad OTH exome AF: 0.000297

GnomAD4 exome AF: 0.000279 AC: 380 AN: 1360974 Hom.: 0 Cov.: 31 AF XY: 0.000276 AC XY: 185 AN XY: 669254

Gnomad4 AFR exome AF: 0.000101

Gnomad4 AMR exome AF: 0.000469

Gnomad4 ASJ exome AF: 0.0000844

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000478

Gnomad4 NFE exome AF: 0.000327

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74362

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000599 Hom.: 0

Bravo AF: 0.000317

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 18, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Uncertain:2 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 01, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 10, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -

Peutz-Jeghers syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 16, 2014	The c.*8C>T variant is located in the 3' untranslated region (3 UTR) of the STK11 gene. This variant results from a C to T substitution the last translated codon. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 4744 samples (9488 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 46000 alleles tested) in our clinical cohort. This nucleotide position is not well conserved in available vertebrate species, and thymine is the reference nucleotide in several species. Since supporting evidence is limited at this time, the clinical significance of c.*8C>T remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2015	- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Sep 12, 2022

- -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The STK11 c.*8C>T variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, Insight Hereditary Tumors Database, databases. The variant was identified in dbSBP (ID: rs587782259) “With Uncertain significance” allele, ClinVar (classified with conflicting interpretations of pathogenicity; classified benign by GeneDx, likely benign by Illumina and uncertain significance by Ambry Genetics), Clinvitae (3x), and in control databases in 42 of 138760 chromosomes at a frequency of 0.0003 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), identified in the following populations: African in 1 of 13784 chromosomes (frequency: 0.00007), Other in 2 of 3874 chromosomes (frequency: 0.0005), Latino in 11 of 18642 chromosomes (frequency: 0.0006), European (Non-Finnish) in 26 of 55232 chromosomes (frequency: 0.0005), and Ashkenazi Jewish in 2 of 6458 chromosomes (frequency: 0.0003). The variant occurs 8 nucleotides downstream of the final codon, outside of the splicing consensus sequence, and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.0
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587782259; hg19: chr19-1226654;