rs536282050

Positions:

• chr19-1220518-TA-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000455.5(STK11):​c.597+14del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000657 in 1,596,188 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: STK11 NM_000455.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -2.22

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 -16 ACMG points.

• BP6: Variant 19-1220518-TA-T is Benign according to our data. Variant chr19-1220518-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 182881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1220518-TA-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000683 (104/152198) while in subpopulation AMR AF= 0.00203 (31/15296). AF 95% confidence interval is 0.00147. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 104 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.597+14del		intron_variant		ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.597+14del		intron_variant			NP_001394184.1
STK11	NR_176325.1	n.1864+14del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.597+14del		intron_variant		1	NM_000455.5	ENSP00000324856	P1

Frequencies

GnomAD3 genomes AF: 0.000684 AC: 104 AN: 152078 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000590 AC: 129 AN: 218518 Hom.: 0 AF XY: 0.000520 AC XY: 62 AN XY: 119168

Gnomad AFR exome AF: 0.000239

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.000186

Gnomad SAS exome AF: 0.000179

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000507

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000654 AC: 945 AN: 1443990 Hom.: 0 Cov.: 32 AF XY: 0.000652 AC XY: 467 AN XY: 716506

Gnomad4 AFR exome AF: 0.000452

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.00117

Gnomad4 EAS exome AF: 0.000180

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.0000197

Gnomad4 NFE exome AF: 0.000679

Gnomad4 OTH exome AF: 0.000873

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000578 AC XY: 43 AN XY: 74420

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000291 Hom.: 0

Bravo AF: 0.000695

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	STK11: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 19, 2017	- -

Peutz-Jeghers syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 25, 2016	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 01, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2014	The variant is found in BR-OV-HEREDIC,COLO-HEREDIC panel(s). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 06, 2014	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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 31, 2023

- -

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.597+14delA variant was not identified in the literature nor was it identified in the Cosmic, MutDB, Zhejiang Colon Cancer Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs536282050) as “With Likely benign allele,” ClinVar (as benign by GeneDx and likely benign by Illumina, Counsyl, and Color Genomics), Clinvitae (2x as in ClinVar), and LOVD 3.0 (2x as likely benign) databases. The variant was identified in control databases in 1 of 30810 chromosomes at a frequency of 0.000032 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 8678 chromosomes (freq: 0.000115), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (Non-Finnish), Latino, Other, and South Asian populations. The variant occurs 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. The variant was identified with a co-occurring pathogenic NBN variant (p.Lys233SerfsX5), increasing the likelihood that the c.597+14delA variant does not have clinical significance. 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

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: rs536282050; hg19: chr19-1220517;